WO2019173551A1 - Formes cristallines d'un stimulateur de sgc - Google Patents

Formes cristallines d'un stimulateur de sgc Download PDF

Info

Publication number
WO2019173551A1
WO2019173551A1 PCT/US2019/021080 US2019021080W WO2019173551A1 WO 2019173551 A1 WO2019173551 A1 WO 2019173551A1 US 2019021080 W US2019021080 W US 2019021080W WO 2019173551 A1 WO2019173551 A1 WO 2019173551A1
Authority
WO
WIPO (PCT)
Prior art keywords
crystalline
fluorobenzyl
imidazo
trifluoromethyl
triazol
Prior art date
Application number
PCT/US2019/021080
Other languages
English (en)
Other versions
WO2019173551A8 (fr
Inventor
Kwame W. NTI-ADDAE
Leena Kumari PRASAD
Thomas Storz
Original Assignee
Cyclerion Therapeutics, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to EP19712427.4A priority Critical patent/EP3762389B1/fr
Priority to MX2020009183A priority patent/MX2020009183A/es
Application filed by Cyclerion Therapeutics, Inc. filed Critical Cyclerion Therapeutics, Inc.
Priority to JP2020546378A priority patent/JP7423539B2/ja
Priority to CR20200458A priority patent/CR20200458A/es
Priority to US16/976,430 priority patent/US11466015B2/en
Priority to MX2023004856A priority patent/MX2023004856A/es
Priority to PE2020001347A priority patent/PE20210124A1/es
Priority to KR1020207028170A priority patent/KR20200128708A/ko
Priority to SG11202008641WA priority patent/SG11202008641WA/en
Priority to MX2023004857A priority patent/MX2023004857A/es
Priority to ES19712427T priority patent/ES2980256T3/es
Priority to CN201980017657.XA priority patent/CN111836812A/zh
Priority to CA3092683A priority patent/CA3092683A1/fr
Priority to AU2019231724A priority patent/AU2019231724B2/en
Priority to EA202092109A priority patent/EA202092109A1/ru
Priority to BR112020018212-5A priority patent/BR112020018212A2/pt
Priority to MX2023004855A priority patent/MX2023004855A/es
Priority to MX2023004858A priority patent/MX2023004858A/es
Publication of WO2019173551A1 publication Critical patent/WO2019173551A1/fr
Publication of WO2019173551A8 publication Critical patent/WO2019173551A8/fr
Priority to IL276853A priority patent/IL276853A/en
Priority to PH12020551394A priority patent/PH12020551394A1/en
Priority to CONC2020/0012493A priority patent/CO2020012493A2/es
Priority to US17/954,713 priority patent/US12122782B2/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • sGC is the primary receptor for NO in vivo.
  • NO guanosine-5'-triphosphate
  • the increased level of cGMP modulates the activity of downstream effectors including protein kinases, phosphodiesterases (PDEs) and ion channels.
  • PDEs protein kinases
  • NOS nitric oxide synthase
  • sGC stimulators are heme-dependent agonists of the sGC enzyme that work synergistically with varying amounts of NO to increase its enzymatic conversion of GTP to cGMP. sGC stimulators are clearly differentiated from and structurally unrelated to another class of NO-independent, heme-independent agonists of sGC known as sGC activators.
  • One such sGC stimulator is 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- 1,2,4- triazol-5-yl)imidazo[l,2-a]pyrazine, depicted below as a compound of Formula (I):
  • Also provided herein is a novel crystalline ethanol solvate of 8-(2-fluorobenzyl)-6-(3- (trifluoromethyl)- 1H- 1 ,2,4-triazol-5-yl)imidazo[ 1 ,2-a]pyrazine.
  • Also provided herein is a novel crystalline acetonitrile solvate of 8-(2-fluorobenzyl)- 6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine.
  • compositions comprising crystalline Form A of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)- 1 H- 1 ,2,4-triazol-5-yl)imidazo[ 1 ,2-a]pyrazine, methods for their manufacture, and uses thereof for treating various diseases, wherein an increase in the concentration of nitric oxide (NO) or an increase in the concentration of cyclic Guanosine 3’,5’-Monophosphate (cGMP) or both, or an upregulation of the NO pathway is desirable, such as, e.g., CNS diseases.
  • NO nitric oxide
  • cGMP cyclic Guanosine 3’,5’-Monophosphate
  • compositions comprising crystalline Form B of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine, methods for their manufacture, and uses thereof for treating various diseases, wherein an increase in the concentration of nitric oxide (NO) or an increase in the concentration of cyclic Guanosine 3’,5’-Monophosphate (cGMP) or both, or an upregulation of the NO pathway is desirable, such as, e.g., CNS diseases.
  • NO nitric oxide
  • cGMP cyclic Guanosine 3’,5’-Monophosphate
  • compositions comprising crystalline Hydrate 1 of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2- a]pyrazine, methods for their manufacture, and uses thereof for treating various diseases, wherein an increase in the concentration of nitric oxide (NO) or an increase in the concentration of cyclic Guanosine 3’,5’-Monophosphate (cGMP) or both, or an upregulation of the NO pathway is desirable, such as, e.g., CNS diseases.
  • NO nitric oxide
  • cGMP cyclic Guanosine 3’,5’-Monophosphate
  • compositions comprising crystalline Hydrate 2 of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2- a]pyrazine, methods for their manufacture, and uses thereof for treating various diseases, wherein an increase in the concentration of nitric oxide (NO) or an increase in the concentration of cyclic Guanosine 3’,5’-Monophosphate (cGMP) or both, or an upregulation of the NO pathway is desirable, such as, e.g., CNS diseases.
  • NO nitric oxide
  • cGMP cyclic Guanosine 3’,5’-Monophosphate
  • compositions comprising crystalline Hydrate 3 of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2- a]pyrazine, methods for their manufacture, and uses thereof for treating various diseases, wherein an increase in the concentration of nitric oxide (NO) or an increase in the concentration of cyclic Guanosine 3’,5’-Monophosphate (cGMP) or both, or an upregulation of the NO pathway is desirable, such as, e.g., CNS diseases (e.g., Alzheimer’s disease and mixed dementia).
  • CNS diseases e.g., Alzheimer’s disease and mixed dementia
  • compositions comprising crystalline ethanol solvate, crystalline methanol solvate, crystalline methyl ethyl ketone solvate, crystalline dichloromethane solvate, or crystalline acetonitrile solvate of 8-(2-fluorobenzyl)- 6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine, methods for their manufacture, and uses thereof for treating various diseases, wherein an increase in the concentration of nitric oxide (NO) or an increase in the concentration of cyclic Guanosine 3’,5’-Monophosphate (cGMP) or both, or an upregulation of the NO pathway is desirable, such as, e.g., CNS diseases.
  • NO nitric oxide
  • cGMP cyclic Guanosine 3’,5’-Monophosphate
  • FIG. 1A depicts an X-ray powder diffraction pattern (XRPD) pattern of 8-(2- fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine Form A, acquired at room temperature in reflection mode using a Bruker D8 Discover system.
  • XRPD X-ray powder diffraction pattern
  • FIG. 1B depicts an X-ray powder diffraction pattern (XRPD) pattern of 8-(2- fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine Form A, acquired at room temperature in reflection mode using a Panalytical Empyrean system.
  • XRPD X-ray powder diffraction pattern
  • FIG. 2 depicts a differential scanning calorimetry (DSC) analysis of 8-(2- fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine Form A.
  • DSC differential scanning calorimetry
  • FIG. 3 depicts a thermal gravimetric analysis (TGA) of 8-(2-fluorobenzyl)-6-(3- (trifluoromethyl)- 1H- 1 ,2,4-triazol-5-yl)imidazo[ 1 ,2-a]pyrazine Form A.
  • TGA thermal gravimetric analysis
  • FIG. 4 depicts a dynamic vapor sorption (DVS) analysis of 8-(2-fluorobenzyl)-6-(3- (trifluoromethyl)- 1H- 1 ,2,4-triazol-5-yl)imidazo[ 1 ,2-a]pyrazine Form A.
  • DVD dynamic vapor sorption
  • FIG. 5A depicts an XRPD pattern of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine Form B, acquired at room temperature in reflection mode using a Bruker D8 Discover system.
  • FIG. 5B depicts an X-ray powder diffraction pattern (XRPD) pattern of 8-(2- fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine Form B, acquired at room temperature in reflection mode using a Panalytical Empyrean system.
  • XRPD X-ray powder diffraction pattern
  • FIG. 6 depicts a DSC analysis of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- 1,2,4- triazol-5-yl)imidazo[l,2-a]pyrazine Form B.
  • FIG. 7 depicts a TGA analysis of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- 1,2,4- triazol-5-yl)imidazo[l,2-a]pyrazine Form B.
  • FIG. 8A depicts an XRPD pattern of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine Hydrate 1, acquired at room temperature in reflection mode using a Bruker D8 Discover system.
  • FIG. 8B depicts an X-ray powder diffraction pattern (XRPD) pattern of 8-(2- fluorobenzyl)-6-(3-(trifluoromethyl)- 1H- 1 ,2,4-triazol-5-yl)imidazo[ 1 ,2-a]pyrazine Hydrate 1 , acquired at room temperature in reflection mode using a Panalytical Empyrean system.
  • XRPD X-ray powder diffraction pattern
  • FIG. 9 depicts a DSC analysis of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- 1,2,4- triazol-5-yl)imidazo[l,2-a]pyrazine Hydrate 1.
  • FIG. 10 depicts a TGA analysis of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine Hydrate 1.
  • FIG. 11A is an XRPD pattern of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- 1,2,4- triazol-5-yl)imidazo[l,2-a]pyrazine Hydrate 2, acquired at room temperature in reflection mode using a Bruker D8 Discover system.
  • FIG. 11B depicts an X-ray powder diffraction pattern (XRPD) pattern of 8-(2- fluorobenzyl)-6-(3-(trifluoromethyl)- 1H- 1 ,2,4-triazol-5-yl)imidazo[ 1 ,2-a]pyrazine Hydrate 2, acquired at room temperature in reflection mode using a Panalytical Empyrean system.
  • XRPD X-ray powder diffraction pattern
  • FIG. 12 is a DSC analysis of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- 1,2,4- triazol-5-yl)imidazo[l,2-a]pyrazine Hydrate 2.
  • FIG. 13 is a TGA analysis of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- 1,2,4- triazol-5-yl)imidazo[l,2-a]pyrazine Hydrate 2.
  • FIG. 14A is a XRPD pattern of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4- triazol-5-yl)imidazo[l,2-a]pyrazine Hydrate 3, acquired at room temperature in reflection mode using a Bruker D8 Discover system.
  • FIG. 14B depicts an X-ray powder diffraction pattern (XRPD) pattern of 8-(2- fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine Hydrate 3, acquired at room temperature in reflection mode using a Panalytical Empyrean system.
  • XRPD X-ray powder diffraction pattern
  • FIG. 15 is a DSC analysis of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- 1,2,4- triazol-5-yl)imidazo[l,2-a]pyrazine Hydrate 3.
  • FIG. 16 is a TGA analysis of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- 1,2,4- triazol-5-yl)imidazo[l,2-a]pyrazine Hydrate 3.
  • FIG. 17 is a XRPD pattern of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- 1,2,4- triazol-5-yl)imidazo[l,2-a]pyrazine ethanol solvate, acquired at room temperature in reflection mode using a Bruker D8 Discover system.
  • FIG. 18 is a TGA analysis of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- 1,2,4- triazol-5-yl)imidazo[l,2-a]pyrazine ethanol solvate.
  • FIG. 19 is a XRPD pattern of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- 1,2,4- triazol-5-yl)imidazo[l,2-a]pyrazine methanol solvate, acquired at room temperature in reflection mode using a Bruker D8 Discover system.
  • FIG. 20 is a TGA analysis of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- 1,2,4- triazol-5-yl)imidazo[l,2-a]pyrazine methanol solvate.
  • FIG. 21 is a XRPD pattern of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- 1,2,4- triazol-5-yl)imidazo[l,2-a]pyrazine methyl ethyl ketone solvate, acquired at room
  • FIG. 22 is a XRPD pattern of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- 1,2,4- triazol-5-yl)imidazo[l,2-a]pyrazine dichloromethane solvate, acquired at room temperature in reflection mode using a Bruker D8 Discover system.
  • FIG. 23 is a TGA analysis of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- 1,2,4- triazol-5-yl)imidazo[l,2-a]pyrazine dichloromethane solvate.
  • FIG. 24 is a XRPD pattern of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- 1,2,4- triazol-5-yl)imidazo[l,2-a]pyrazine acetonitrile solvate, acquired at room temperature in reflection mode using a Bruker D8 Discover system.
  • FIG. 25 is a TGA analysis of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- 1,2,4- triazol-5-yl)imidazo[l,2-a]pyrazine acetonitrile solvate.
  • FIG. 26 is a XRPD pattern of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- 1,2,4- triazol-5-yl)imidazo[l,2-a]pyrazine ethyl acetate solvate, acquired at room temperature in reflection mode using a Bruker D8 Discover system.
  • FIG. 27 is a TGA analysis of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- 1,2,4- triazol-5-yl)imidazo[l,2-a]pyrazine ethyl acetate solvate.
  • Form A refers to the crystalline polymorph Form A of 8- (2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine.
  • Form A “Form A”,“Form A of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol- 5-yl)imidazo[l,2-a]pyrazine”, and“crystalline Form A of 8-(2-fluorobenzyl)-6-(3- (trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine” are intended to include only an anhydrous form of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5- yl)imidazo[l,2-a]pyrazine as the free form.
  • Form A can be characterized by, for example, XRPD alone or XRPD in combination with any one or more of DSC, DVS, and TGA.
  • Form B refers to the crystalline polymorph Form B of 8- (2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine.
  • Form B can be characterized by, for example, XRPD alone or XRPD in combination with any one or more of DSC, and TGA.
  • “Hydrate 1” refers to the crystalline polymorph Hydrate 1 of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine.
  • the terms“Hydrate 1”,“crystalline Hydrate 1”, and“crystalline Hydrate 1 of 8-(2- fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine are used interchangeably.
  • Hydrate 1 can be characterized by, for example, XRPD alone or XRPD in combination with any one or more of DSC, and TGA.
  • “Hydrate 2” refers to the crystalline polymorph Hydrate 2 of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine.
  • the terms“Hydrate 2”,“crystalline Hydrate 2”, and“crystalline Hydrate 2 of 8-(2- fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine are used interchangeably.
  • Hydrate 2 can be characterized by, for example, XRPD alone or XRPD in combination with any one or more of DSC, and TGA.
  • “Hydrate 3” refers to the crystalline polymorph Hydrate 3 of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine.
  • the terms“Hydrate 3”,“crystalline Hydrate 3”, and“crystalline Hydrate 3 of 8-(2- fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine are used interchangeably.
  • Hydrate 3 can be characterized by, for example, XRPD alone or XRPD in combination with any one or more of DSC, and TGA.
  • Form A and Form B refers to a crystalline solid adduct containing only 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5- yl)imidazo[l,2-a]pyrazine (i.e., the compound of Formula (I)).
  • crystalline refers to a solid having a crystal structure wherein the individual molecules have a highly homogeneous regular locked-in chemical configuration.
  • “Anhydrous” as used herein, means that the crystalline form comprises substantially no water in the crystal lattice e.g., less than 1% by weight as determined by Karl Fisher (KF), or less than 1% by weight as determined by another quantitative analysis.
  • solvate as in crystalline ethanol solvate, crystalline methanol solvate, crystalline methyl ethyl ketone solvate, crystalline dichloromethane solvate, and crystalline acetonitrile solvate refers to a crystalline solid adduct containing a compound of Formula (I) and either stoichiometric or nonstoichiometric amounts of a solvent incorporated within the crystal structure.
  • Techniques known to one of skill in the art to determine the to determine the amount of solvent present include, for example, HPLC,
  • Hydrate 1 refers to a crystalline solid adduct containing a compound of Formula (I) and either stoichiometric or nonstoichiometric amounts of a water incorporated within the crystal structure.
  • Techniques known to one of skill in the art to determine the to determine the amount of water present include, for example, TGA and KF.
  • Solid state ordering of solids may be determined by standard techniques known in the art, e.g., by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), or thermal gravimetric analysis (TGA).
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • TGA thermal gravimetric analysis
  • Amorphous solids can also be differentiated from crystalline solids e.g., by birefringence using polarized light microscopy.
  • Amorphous solids consist of disordered arrangements of molecules and do not possess a distinguishable crystal lattice.
  • Relative intensity is calculated as a ratio of the peak intensity of the peak of interest versus the peak intensity of the largest peak.
  • the relative intensity of the peaks may vary due to the preferred orientation of the sample. Preferred orientation in the specimen influences the intensities of various reflections so that some are more intense and others less intense, compared to what would be expected from a completely random specimen. In general, the morphology of many crystalline particles tends to give a specimen that exhibits some degree of preferred orientation in the specimen holder. This is particularly evident for needlelike or plate-like crystals when size reduction yields finer needles or platelets.
  • the XRPD patterns are acquired at room temperature in reflection mode using a Bruker D8 Discover system equipped with a sealed tube source and a Hi-Star area detector (Bruker AXS, Madison, WI).
  • the X-Ray generator was operated at a voltage of 40 kV and a current of 40 mA with a Cu-anode as X-ray source (CuKal radiation, l ⁇ I.54056 A, 40 kV, 40 mA).
  • the powder sample was placed in a low-background holder.
  • the data was subsequently integrated over the range of 5.000° - 45.000° 20 with a step size of 0.020° and merged into one continuous pattern.
  • XRPD patterns are acquired at room temperature in reflection mode using a Panalytical Empyrean system equipped with a sealed tube source and a PIXcel 10 detector.
  • the X-Ray generator is operated at a voltage of 45 kV and a current of 40 mA with a Cu-anode as X-ray source (CuKal radiation, l ⁇ I.54056
  • the powder sample is placed in a zero-background holder.
  • the data is subsequently integrated over the range of 4.0° - 40.0° 20 with a step size of 0.026° and merged into one continuous pattern.
  • Form A is at least 70%, 80%, 90%, 95%, 98%, 99%, 99.5%, or 99.9% pure.
  • the purity of Form A is determined by dividing the weight of Form A of the compound of Formula (I) in a composition comprising the compound of Formula (I) over the total weight of the compound of Formula (I) in the composition.
  • Form B is at least 70%, 80%, 90%, 95%, 98%, 99%, 99.5%, or 99.9% pure.
  • the purity of Form B is determined by dividing the weight of Form B of the compound of Formula (I) in a composition comprising the compound of Formula (I) over the total weight of the compound of Formula (I) in the composition.
  • Hydrate 1 is at least 70%, 80%, 90%, 95%, 98%, 99%, 99.5%, or 99.9% pure.
  • the purity of Hydrate 1 is determined by dividing the weight of Hydrate 1 of the compound of Formula (I) in a composition comprising the compound of Formula (I) over the total weight of the compound of Formula I in the composition.
  • Hydrate 2 is at least 70%, 80%, 90%, 95%, 98%, 99%, 99.5%, or 99.9% pure.
  • the purity of Hydrate 2 is determined by dividing the weight of Hydrate 2 of the compound of Formula (I) in a composition comprising the compound of Formula (I) over the total weight of the compound of Formula (I) in the composition.
  • Hydrate 3 is at least 70%, 80%, 90%, 95%, 98%, 99%, 99.5%, or 99.9% pure.
  • the purity of Hydrate 3 is determined by dividing the weight of Hydrate 3 of the compound of Formula (I) in a composition comprising the compound of Formula (I) over the total weight of the compound of Formula (I) in the composition.
  • crystalline ethanol solvate, crystalline methanol solvate, crystalline methyl ethyl ketone solvate, crystalline dichloromethane solvate, or crystalline acetonitrile solvate is at least 70%, 80%, 90%, 95%, 98%, 99%, 99.5%, or 99.9% pure.
  • the purity of crystalline ethanol solvate, crystalline methanol solvate, crystalline methyl ethyl ketone solvate, crystalline dichloromethane solvate, or crystalline acetonitrile solvate is determined by dividing the weight of crystalline ethanol solvate, crystalline methanol solvate, crystalline methyl ethyl ketone solvate, crystalline dichloromethane solvate, or crystalline acetonitrile solvate of the compound of Formula (I) in a composition comprising the compound of Formula (I) over the total weight of the compound of Formula (I) in the composition.
  • Form A and Form B are more stable than the ethyl acetate solvate.
  • Form A, Form B, Hydrate 1, Hydrate 2, and Hydrate 3 are all suitable for pharmaceutical use, whereas the ethyl acetate solvate is incompatible with a formulation for human use.
  • Other advantages may include favorable pharmacokinetic properties, ease of isolation, process reproducibility, suitability for large scale manufacturing process, etc.
  • the present disclosure provides crystalline Form A of 8-(2- fluorobenzyl)-6-(3-(trifluoromethyl)- 1H- 1 ,2,4-triazol-5-yl)imidazo[ 1 ,2-a]pyrazine.
  • crystalline Form A of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine is characterized by x-ray powder diffraction pattern.
  • the x-ray powder diffraction pattern can be acquired at room temperature in reflection mode using a Bruker D8 Discover system described herein.
  • crystalline Form A is characterized by at least three, at least four, or at least five x-ray powder diffraction peaks at 2Q angles selected from 7.0°, 8.3°, 11.1°, 14.3°, and 15.0°.
  • crystalline Form A is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten x-ray powder diffraction peaks at 2Q angles 7.0°, 8.3°, 11.1°, 14.3°, 15.0°, 15.9°, 16.7°, 17.6°, 19.1°, 20.2°, 21.6°, 24.9°, and 25.8°.
  • crystalline Form A is characterized by x-ray powder diffraction peaks at 2Q angles 7.0°, 8.3°, 11.1°, 14.3°, 15.0°, 15.9°, 16.7°, 17.6°, 19.1°, 20.2°, 21.6°, 24.9°, and 25.8°.
  • crystalline Form A is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine x-ray powder diffraction peaks at 2Q angles 7.0°, 8.3°, 11.1°, 14.3°, 15.0°, 17.6°, 19.1°, 20.2°, and 21.6°.
  • crystalline Form A is characterized by x-ray powder diffraction peaks at 2Q angles 7.0°, 8.3°, 11.1°, 14.3°, 15.0°, 17.6°, 19.1°, 20.2°, and 21.6°.
  • crystalline Form A is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten x-ray powder diffraction peaks at 2Q angles selected from 4.9°, 7.0°, 8.3°, 10.6°, 11.1°, 14.3°, 15.0°, 15.9°, 16.7°, 17.6°, 18.2°, 19.1°, 19.7°, 20.2°, 21.6°, 23.2°, 24.9°, 25.8°, 27.1°, 28.2°, 28.8°, 29.9°, 30.8°, 32.1°, and 33.1°.
  • crystalline Form A is characterized by x-ray powder diffraction peaks at 2Q angles 4.9°, 7.0°, 8.3°, 10.6°, 11.1°, 14.3°, 15.0°, 15.9°, 16.7°, 17.6°, 18.2°,
  • the peaks described above for crystalline Form A have a relative intensity of at least 10%, of at least 15%, of at least 20%, or of at least 25%.
  • crystalline Form A of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)- lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has an XRPD pattern that is substantially the same XRPD pattern shown in FIG. 1A.
  • crystalline Form A of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)- lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has an XRPD pattern that substantially includes the peaks in Table 1A.
  • crystalline Form A of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine is characterized by x-ray powder diffraction pattern, acquired at room temperature in reflection mode using a Panalytical Empyrean system described herein.
  • crystalline Form A is characterized by at least three, at least four, or at least five x-ray powder diffraction peaks at 2Q angles selected from 8.3°, 8.5°, 11.3°, 15.0°, 15.2°, and 19.3°.
  • crystalline Form A is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten x-ray powder diffraction peaks at 2Q angles 7.0°, 8.3°, 8.5°, 11.3°, 15.0°, 15.2°, 16.2°, 17.0°, 17.8°, 19.3°, 19.9°, 21.6°, 22.0°, and 22.2°.
  • crystalline Form A is characterized by x-ray powder diffraction peaks at 2Q angles 7.0°, 8.3°, 8.5°,
  • crystalline Form A is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten x-ray powder diffraction peaks at 2Q angles selected from 5.0°, 7.0°, 7.2°, 8.3°, 8.5°, 10.4°, 10.8°, 11.3°, 12.4°, 14.2°, 14.4°, 14.6°, 15.0°, 15.2°, 16.2°, 17.0°, 17.8°, 18.5°, 19.3°, 19.9°, 20.3°, 21.6°, 22.0°, 22.2°, 22.6°, 22.9°,
  • the peaks described above for crystalline Form A have a relative intensity of at least 10%, of at least 15%, of at least 20%, or of at least 25%.
  • crystalline Form A of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)- lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has an XRPD pattern that is substantially the same XRPD pattern shown in FIG. 1B.
  • crystalline Form A of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)- lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has an XRPD pattern that substantially includes the peaks in Table 1B.
  • crystalline Form A of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has a DSC pattern that is substantially the same DSC pattern shown in FIG. 2.
  • crystalline Form A is characterized by DSC melting temperature of 195° C ⁇ 2° C.
  • crystalline Form A of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has a TGA pattern that is substantially the same TGA pattern shown in FIG. 3.
  • crystalline Form A of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has a DVS pattern that is substantially the same DVS pattern shown in FIG. 4.
  • the crystalline Form A of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine is characterized by at least three, at least four, or by at least five, x-ray powder diffraction peaks at 2Q angles selected from 7.0°, 8.3°, 11.1°,
  • crystalline Form A is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten x-ray powder diffraction peaks at 2Q angles selected from 7.0°, 8.3°, 11.1°, 14.3°, 15.0°, 15.9°, 16.7°, 17.6°, 19.1°, 20.2°, 21.6°, 24.9°, and 25.8° optionally together with one, two, or three of the TGA, DSC, DVS parameters recited above for Form A.
  • the crystalline Form A of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine is characterized by at least three, at least four, or by at least five, x-ray powder diffraction peaks at 2Q angles selected from 8.3, 8.5°, 11.3°, 15.0°, 15.2°, and 19.3°; optionally together with one, two, or three of the TGA, DSC, DVS parameters recited above for Form A.
  • crystalline Form A is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten x-ray powder diffraction peaks at 2Q angles selected from 7.0°, 8.3°, 8.5°, 11.3°, 15.0°, 15.2°, 16.2°, 17.0°, 17.8°, 19.3°, 19.9°, 21.6°, 22.0°, and 22.2° optionally together with one, two, or three of the TGA, DSC, DVS parameters recited above for Form A.
  • the crystalline Form A of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine x-ray powder diffraction peaks at 20 angles 7.0°, 8.3°, 11.1°, 14.3°, 15.0°, 17.6°, 19.1°, 20.2°, and 21.6° optionally together with one, two, or three of the TGA, DSC, DVS parameters recited above for Form A.
  • crystalline Form B of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine is characterized by x-ray powder diffraction pattern.
  • the x-ray powder diffraction pattern can be acquired at room temperature in reflection mode using a Bruker D8 Discover system described herein.
  • crystalline Form B is characterized by at least three, at least four, or at least five x-ray powder diffraction peaks at 2Q angles selected from 8.9°, 12.2°, 13.6°, 17.2°, and 21.0°.
  • crystalline Form B is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten x-ray powder diffraction peaks at 20 angles selected from 8.9°, 12.2°, 13.6°, 14.5°, 15.7°, 17.2°, 17.7°, 21.0°, 22.7°, 23.9°, 25.0°, 26.7°, and 27.6°.
  • crystalline Form B is characterized by x-ray powder diffraction peaks at 2Q angles 8.9°, 12.2°, 13.6°, 14.5°, 15.7°, 17.2°, 17.7°, 21.0°, 22.7°, 23.9°, 25.0°, 26.7°, and 27.6°.
  • crystalline Form B is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine, x-ray powder diffraction peaks at 2Q angles selected from 8.9°, 12.2°, 13.6°, 14.5°, 15.7°, 17.2°, 21.0°, 22.7°, and 23.9°.
  • crystalline Form B is characterized by x-ray powder diffraction peaks at 2Q angles 8.9°, 12.2°, 13.6°, 14.5°, 15.7°, 17.2°, 21.0°, 22.7°, and 23.9°.
  • crystalline Form B is characterized by x-ray powder diffraction peaks at 2Q angles 8.9°, 12.2°, 13.6°, 14.5°, 15.7°, 17.2°, 17.7°, 18.3°, 21.0°, 22.7°, 23.9°, 24.2°, 25.0°, 25.6°, 26.7°, 27.6°, and 29.6°.
  • the peaks described above for crystalline Form B have a relative intensity of at least 10%, of at least 15%, of at least 20%, or of at least 25%.
  • crystalline Form B of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has an XRPD pattern that is substantially the same XRPD pattern shown in FIG. 5A.
  • crystalline Form B of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has an XRPD pattern that substantially includes the peaks in Table 2A.
  • crystalline Form B of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine is characterized by x-ray powder diffraction pattern, acquired at room temperature in reflection mode using a Panalytical Empyrean system described herein.
  • crystalline Form B is characterized by at least three, at least four, or at least five x-ray powder diffraction peaks at 2Q angles selected from 13.8°, 16.0°, 17.4°, 18.0°, 18.5°, and 21.2°.
  • crystalline Form B is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten x-ray powder diffraction peaks at 2Q angles selected from 9.1°, 10.9°, 12.4°, 13.8°, 14.8°, 16.0°, 17.4°, 18.0°, 18.5°, 21.2°, 22.9°, 24.1°, 24.5°, 27.8°, 30.0°.
  • crystalline Form B is characterized by x-ray powder diffraction peaks at 2Q angles 9.1°, 10.9°, 12.4°, 13.8°, 14.8°, 16.0°, 17.4°, 18.0°, 18.5°, 21.2°, 22.9°, 24.1°, 24.5°, 27.8°, 30.0°.
  • crystalline Form B is characterized by x-ray powder diffraction peaks at 2Q angles 8.5°, 9.1°, 10.9°, 12.4°, 13.8°, 14.6°, 14.8°, 15.7°, 16.0°, 17.4°, 18.0°, 18.2°, 18.5°, 20.4°, 21.2°, 22.1°, 22.6°, 22.9°, 23.5°, 24.1°, 24.5°, 25.2°, 25.7°, 25.9°, 26.8°, 27.1°, 27.8°, 28.8°, 29.4°, 29.7°, 30.0°, 31.1°, 31.6°, 32.3°, 33.5°, 34.0°, 35.2°, 35.7°, 36.8°, and 38.0°.
  • the peaks described above for crystalline Form B have a relative intensity of at least 10%, of at least 15%, of at least 20%, or of at least 25%.
  • crystalline Form B of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has an XRPD pattern that is substantially the same XRPD pattern shown in FIG. 5B.
  • crystalline Form B of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has an XRPD pattern that substantially includes the peaks in Table 2B.
  • crystalline Form B of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has a DSC pattern that is substantially the same DSC pattern shown in FIG. 6.
  • crystalline Form B is characterized by DSC phase transition temperature of 177°+ 2° C and a melt at 195° C ⁇ 2° C.
  • crystalline Form B of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has a TGA pattern that is substantially the same TGA pattern shown in FIG. 7.
  • the crystalline Form B of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine is characterized by at least three, at least four, or by at least five, x-ray powder diffraction peaks at 2Q angles selected from 8.9°, 12.2°, 13.6°, 17.2°, and 21.0°; optionally together with one or both of the TGA, and DSC parameters recited above for Form B.
  • crystalline Form B is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten x-ray powder diffraction peaks at 2Q angles selected from 8.9°, 12.2°, 13.6°, 14.5°, 15.7°, 17.2°, 17.7°, 21.0°, 22.7°, 23.9°, 25.0°, 26.7°, and 27.6° optionally together with one or both of the TGA, and DSC parameters recited above for Form B.
  • the crystalline Form B of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine is characterized by at least three, at least four, or by at least five, x-ray powder diffraction peaks at 2Q angles selected from 13.8°, 16.0°, 17.4°, 18.0°, 18.5°, and 21.2°; optionally together with one or both of the TGA, and DSC
  • crystalline Form B is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten x-ray powder diffraction peaks at 2Q angles selected from 9.1°, 10.9°, 12.4°,
  • the crystalline Form B of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine x-ray powder diffraction peaks at 20 angles selected from 8.9°, 12.2°, 13.6°, 14.5°, 15.7°, 17.2°, 21.0°, 22.7°, and 23.9°, optionally together with one or both of the TGA, and DSC parameters recited above for Form B.
  • crystalline Hydrate 1 of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine is characterized by x-ray powder diffraction pattern.
  • the x-ray powder diffraction pattern can be acquired at room temperature in reflection mode using a Bruker D8 Discover system described herein.
  • crystalline Hydrate 1 is characterized by at least three, at least four, or at least five x-ray powder diffraction peaks at 2Q angles selected from 11.5°, 15.2°, 17.0°, 17.7°, and 18.3°.
  • crystalline Hydrate 1 of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- 1,2,4- triazol-5-yl)imidazo[l,2-a]pyrazine is characterized by at least three, or at least four x-ray powder diffraction peaks at 2Q angles selected from 11.5°, 15.2°, 17.0°, and 18.3°.
  • crystalline Hydrate 1 is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten x-ray powder diffraction peaks at 2Q angles selected from 11.5°, 13.5°, 15.2°, 17.0°, 17.7°, 18.3°, 19.1°, 22.1°, 23.1°, 23.3°, 24.2°, 24.9°, and 29.4°.
  • crystalline Hydrate 1 is characterized by x-ray powder diffraction peaks at 2Q angles 11.5°, 13.5°, 15.2°, 17.0°,
  • crystalline Hydrate 1 is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten x-ray powder diffraction peaks at 2Q angles selected from 11.5°, 13.5°, 17.0°, 17.7°, 18.3°, 22.1°, 23.1°, 23.3°, 24.2°, 24.9°, and 29.4°.
  • crystalline Hydrate 1 is characterized by x-ray powder diffraction peaks at 2Q angles 11.5°, 13.5°, 17.0°, 17.7°, 18.3°, 22.1°, 23.1°, 23.3°, 24.2°, 24.9°, and 29.4°.
  • crystalline Hydrate 1 is characterized by x-ray powder diffraction peaks at 2Q angles 9.1°, 11.5°, 13.5°, 15.2°, 17.0°, 17.7°, 18.3°, 19.1°, 20.1°, 22.1°, 23.1°, 23.3°, 24.2°, 24.9°, 25.4°, 26.7°, 27.5°, 29.4°, 29.9°, 30.6°, and 33.5°.
  • the peaks described above for crystalline Hydrate 1 have a relative intensity of at least 10%, of at least 15%, of at least 20%, or of at least 25%.
  • crystalline Hydrate 1 of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)- lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has an XRPD pattern that is substantially the same XRPD pattern shown in FIG. 8A.
  • crystalline Hydrate 1 of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)- lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has an XRPD pattern that substantially includes the peaks in Table 3 A.
  • crystalline Hydrate 1 of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine is characterized by x-ray powder diffraction pattern, acquired at room temperature in reflection mode using a Panalytical Empyrean system described herein.
  • crystalline Hydrate 1 is characterized by at least three, at least four, or at least five x-ray powder diffraction peaks at 2Q angles selected from 11.7°, 15.5°, 17.2°, 17.9°, 18.5°, 23.3°, and 25.1°.
  • crystalline Hydrate 1 of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine is characterized by at least three, or at least four x-ray powder diffraction peaks at 2Q angles selected from 11.7°, 15.5°, 17.2°, 17.9°, 18.5°, 23.3°, and 25.1°
  • crystalline Hydrate 1 is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten x-ray powder diffraction peaks at 2Q angles selected from 9.4°, 11.7°, 13.7°, 15.5°, 17.2°, 17.9°, 18.5°, 22.3°, 23.3°, 24.4°, 25.1°, 29.6°, and 30.1°.
  • crystalline Hydrate 1 is characterized by x-ray powder diffraction peaks at 2Q angles 9.4°, 11.7°, 13.7°, 15.5°, 17.2°, 17.9°, 18.5°, 22.3°, 23.3°, 24.4°, 25.1°, 29.6°, and 30.1°.
  • crystalline Hydrate 1 is characterized by x-ray powder diffraction peaks at 2Q angles 8.8°, 9.4°, 11.7°, 12.2°, 13.7°, 14.0°, 15.5°, 16.7°, 17.2°, 17.9°, 18.5°, 19.4°, 20.3°, 21.4°, 22.3°, 23.3°, 23.6°, 24.4°, 25.1°, 25.6°, 27.0°, 27.7°, 28.6°, 29.6°, 30.1°, 30.9°, 32.2°, 33.6°, 34.0°, 35.0°, 37.6°, and 38.9°.
  • the peaks described above for crystalline Hydrate 1 have a relative intensity of at least 10%, of at least 15%, of at least 20%, or of at least 25%.
  • crystalline Hydrate 1 of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)- lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has an XRPD pattern that is substantially the same XRPD pattern shown in FIG. 8B.
  • crystalline Hydrate 1 of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)- lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has an XRPD pattern that substantially includes the peaks in Table 3B.
  • crystalline Hydrate 1 of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has a DSC pattern that is substantially the same DSC pattern shown in FIG. 9.
  • crystalline Hydrate 1 is characterized by two endotherms in the DSC analysis at 58° ⁇ 2° C, 92° ⁇ 2° C, and a melt at 195° C ⁇ 2° C.
  • crystalline Hydrate 1 of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has a TGA pattern that is substantially the same TGA pattern shown in FIG. 10.
  • the crystalline Hydrate 1 of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)- lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine is characterized by at least three, at least four, or by at least five, x-ray powder diffraction peaks at 2Q angles selected from 11.5°, 15.2°, 17.0°, 17.7°, and 18.3°; optionally together with one or both of the TGA, or DSC parameters recited above for Hydrate 1.
  • crystalline Hydrate 1 is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten x-ray powder diffraction peaks at 2Q angles selected from 11.5°, 13.5°, 15.2°, 17.0°, 17.7°, 18.3°, 19.1°, 22.1°, 23.1°, 23.3°, 24.2°, 24.9°, and 29.4° optionally together with one or both of the TGA, or DSC parameters recited above for Hydrate 1.
  • the crystalline Hydrate 1 of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)- lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine is characterized by at least three, at least four, or by at least five, x-ray powder diffraction peaks at 2Q angles selected from 11.7°, 15.5°, 17.2°, 17.9°, 18.5°, 23.3°, and 25.1°; optionally together with one or both of the TGA, or DSC parameters recited above for Hydrate 1.
  • crystalline Hydrate 1 is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten x-ray powder diffraction peaks at 2Q angles selected from 9.4°, 11.7°, 13.7°, 15.5°, 17.2°, 17.9°, 18.5°, 22.3°, 23.3°, 24.4°, 25.1°, 29.6°, and 30.1°, optionally together with one or both of the TGA, or DSC parameters recited above for Hydrate 1.
  • the crystalline Hydrate 1 of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)- lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten x-ray powder diffraction peaks at 2Q angles selected from 11.5°, 13.5°, 17.0°, 17.7°, 18.3°, 22.1°, 23.1°, 23.3°, 24.2°, 24.9°, and 29.4°; optionally together with one or both of the TGA, or DSC parameters recited above for Hydrate 1.
  • crystalline Hydrate 2 of 8-(2- fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine is characterized by x-ray powder diffraction pattern.
  • the x-ray powder diffraction pattern can be acquired at room temperature in reflection mode using a Bruker D8 Discover system described herein.
  • crystalline Hydrate 2 is characterized by at least three, at least four, or at least five x-ray powder diffraction peaks at 2Q angles selected from 10.4°, 15.5°, 18.4°, 18.7°, and 21.9°.
  • crystalline Hydrate 2 of 8-(2-fluorobenzyl)-6- (3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine is characterized at least three, or at least four x-ray powder diffraction peaks at 2Q angles selected from 10.4°, 15.5°, 18.4°, and 18.7°.
  • crystalline Hydrate 2 is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten x- ray powder diffraction peaks at 2Q angles selected from 10.4°, 15.5°, 18.4°, 18.7°, 20.7°, 21.2°, 21.9°, 22.7°, 24.6°, 25.9°, 26.3°, and 27.4°.
  • crystalline Hydrate 2 is characterized by x-ray powder diffraction peaks at 2Q angles 10.4°, 15.5°, 18.4°, 18.7°,
  • crystalline Hydrate 2 is characterized by at least three, at least four, or at least five x-ray powder diffraction peaks at 2Q angles selected from 10.4°, 18.7°, 21.2°, 24.6°, and 27.4°.
  • crystalline Hydrate 2 is characterized by x-ray powder diffraction peaks at 2Q angles 10.4°, 18.7°, 21.2°, 24.6°, and 27.4°.
  • crystalline Hydrate 2 is characterized by x-ray powder diffraction peaks at 2Q angles 9.0°, 10.4°, 14.9°, 15.5°, 17.8°, 18.4°, 18.7°, 20.7°, 21.2°, 21.9°, 22.7°, 24.6°, 25.9°, 26.3°, 27.4°, 28.0°, 29.5°, 31.0°, 31.7°, 32.6°, and 34.5°.
  • the peaks described above for crystalline Hydrate 2 have a relative intensity of at least 10%, of at least 15%, of at least 20%, or of at least 25%.
  • crystalline Hydrate 2 of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)- lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has an XRPD pattern that is substantially the same XRPD pattern shown in FIG. 11 A.
  • crystalline Hydrate 2 of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)- lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has an XRPD pattern that substantially includes the peaks in Table 4 A.
  • crystalline Hydrate 2 of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine is characterized by x-ray powder diffraction pattern, acquired at room temperature in reflection mode using a Panalytical Empyrean system described herein.
  • crystalline Hydrate 2 is characterized by at least three, at least four, or at least five x-ray powder diffraction peaks at 2Q angles selected from 7.3°, 10.6°, 15.8°, 15.9°, and 27.6°.
  • crystalline Hydrate 2 of 8-(2- fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine is characterized at least three, or at least four x-ray powder diffraction peaks at 2Q angles selected from 7.3°, 10.6°, 15.8°, 15.9°, and 27.6°.
  • crystalline Hydrate 2 is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten x-ray powder diffraction peaks at 2Q angles selected from 7.3°, 10.6°, 15.2°, 15.8°, 15.9°, 18.1°, 18.7°, 19.0°, 23.0°, 24.8°, 25.1°, 26.6°, 27.6°, and 29.8°.
  • crystalline Hydrate 2 is characterized by x-ray powder diffraction peaks at 2Q angles 7.3°, 10.6°, 15.2°, 15.8°, 15.9°, 18.1°, 18.7°, 19.0°, 23.0°, 24.8°, 25.1°, 26.6°, 27.6°, and 29.8°.
  • crystalline Hydrate 2 is characterized by x-ray powder diffraction peaks at 2Q angles 7.3°, 9.3°, 10.6°, 13.2°, 15.2°, 15.8°, 15.9°, 17.1°, 18.1°, 18.7°, 19.0°, 21.0°, 21.5°, 22.2°, 23.0°, 23.8°, 24.8°, 25.1°, 26.2°, 26.6°, 27.6°, 29.8°, 31.2°, 32.0°, 32.8°, 34.6°, 35.1°, and 36.9°.
  • the peaks described above for crystalline Hydrate 2 have a relative intensity of at least 10%, of at least 15%, of at least 20%, or of at least 25%.
  • crystalline Hydrate 2 of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)- lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has an XRPD pattern that is substantially the same XRPD pattern shown in FIG. 11B.
  • crystalline Hydrate 2 of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)- lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has an XRPD pattern that substantially includes the peaks in Table 4B.
  • crystalline Hydrate 2 of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has a DSC pattern that is substantially the same DSC pattern shown in FIG. 12. .
  • crystalline Hydrate 2 is characterized by DSC an endotherm at 87° ⁇ 2° C, and a melt at 195° C ⁇ 2° C.
  • crystalline Hydrate 2 of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has a TGA pattern that is substantially the same TGA pattern shown in FIG. 13.
  • the crystalline Hydrate 2 of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)- lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine is characterized by at least three, at least four, or by at least five, x-ray powder diffraction peaks at 2Q angles selected from 10.4°, 15.5°, 17.8°, 18.4°, and 18.7°; optionally together with one or both of the TGA, or DSC parameters recited above for Hydrate 2.
  • crystalline Hydrate 2 is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten x-ray powder diffraction peaks at 2Q angles selected from 10.4°, 15.5°, 18.4°, 18.7°, 20.7°, 21.2°, 21.9°, 22.7°, 24.6°, 25.9°, 26.3°, and 27.4° optionally together with one or both of the TGA, or DSC parameters recited above for Hydrate 2.
  • the crystalline Hydrate 2 of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)- lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine is characterized by at least three, at least four, or by at least five, x-ray powder diffraction peaks at 2Q angles selected from 7.3°, 10.6°, 15.8°, 15.9°, and 27.6°; optionally together with one or both of the TGA, or DSC parameters recited above for Hydrate 2.
  • crystalline Hydrate 2 is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten x-ray powder diffraction peaks at 2Q angles selected from 7.3°, 10.6°, 15.2°, 15.8°, 15.9°, 18.1°, 18.7°, 19.0°, 23.0°, 24.8°, 25.1°, 26.6°, 27.6°, and 29.8°, optionally together with one or both of the TGA, or DSC parameters recited above for Hydrate 2.
  • the crystalline Hydrate 2 of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)- lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine is characterized by at least three, at least four, or by at least five, x-ray powder diffraction peaks at 2Q angles selected from 10.4°, 18.7°, 21.2°, 24.6°, and 27.4°; optionally together with one or both of the TGA, or DSC parameters recited above for Hydrate 2.
  • crystalline Hydrate 3 of 8-(2-fluorobenzyl)-6-(3- (trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine is characterized by x-ray powder diffraction pattern.
  • the x-ray powder diffraction pattern can be acquired at room temperature in reflection mode using a Bruker D8 Discover system described herein.
  • crystalline Hydrate 3 is characterized by at least three, at least four, or at least five x-ray powder diffraction peaks at 2Q angles selected from 10.3°, 12.1°, 13.5°, 16.9°, and 24.4°.
  • crystalline Hydrate 3 is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten x-ray powder diffraction peaks at 2Q angles selected from 10.3°, 12.1°, 13.5°, 15.9°, 16.9°, 17.6°, 22.0°, 22.9°, 24.4°, and 28.9°.
  • crystalline Hydrate 3 is characterized by x-ray powder diffraction peaks at 2Q angles 10.3°, 12.1°, 13.5°, 15.9°, 16.9°, 17.6°, 22.0°, 22.9°, 24.4°, and 28.9°.
  • crystalline Hydrate 3 is characterized by at least three, or at least four x- ray powder diffraction peaks at 2Q angles selected from 10.3°, 12.1°, 17.6°, and 22.0°.
  • crystalline Hydrate 3 is characterized by x-ray powder diffraction peaks at 2Q angles 10.3°, 12.1°, 17.6°, and 22.0°.
  • crystalline Hydrate 3 is characterized by x-ray powder diffraction peaks at 2Q angles 8.5°, 10.3°, 12.1°, 13.5°, 14.5°, 15.9°, 16.9°, 17.6°, 18.5°, 20.3°, 21.0°, 22.0°, 22.9°, 24.4°, 25.0°, 26.6°, 28.9°, 30.8°, 33.0°, and 36.0°.
  • the peaks described above for crystalline Hydrate 3 have a relative intensity of at least 10%, of at least 15%, of at least 20%, or of at least 25%.
  • crystalline Hydrate 3 of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)- lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has an XRPD pattern that is substantially the same XRPD pattern shown in FIG. 14A.
  • crystalline Hydrate 3 of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)- lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has an XRPD pattern that substantially includes the peaks in Table 5 A.
  • crystalline Hydrate 3 of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine is characterized by x-ray powder diffraction pattern, acquired at room temperature in reflection mode using a Panalytical Empyrean system described herein.
  • crystalline Hydrate 3 is characterized by at least three, at least four, or at least five x-ray powder diffraction peaks at 2Q angles selected from 10.5°, 13.9°, 15.0°, 16.5°, 17.2°, and 17.6°.
  • crystalline Hydrate 3 is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten x-ray powder diffraction peaks at 2Q angles selected from 10.5°, 13.9°, 15.0°, 16.5°, 17.2°, 17.6°, 18.3°, 19.1°, 20.3°, 23.7°, and 30.1°.
  • crystalline Hydrate 3 is characterized by x-ray powder diffraction peaks at 2Q angles 10.5°, 13.9°, 15.0°, 16.5°, 17.2°, 17.6°, 18.3°, 19.1°, 20.3°, 23.7°, and 30.1°.
  • crystalline Hydrate 3 is characterized by x-ray powder diffraction peaks at 2Q angles 8.3°, 8.7°, 10.5°, 12.0°, 12.8°, 13.9°, 14.5°, 15.0°, 16.5°, 17.2°, 17.6°, 18.3°, 19.1°, 20.3°, 21.1°, 21.6°, 22.2°, 22.6°, 23.7°, 24.1°, 24.7°, 25.0°, 25.6°, 26.2°, 27.7°, 28.5°, 30.1°, 31.9°, 34.1°, 35.0°, 35.6°, 37.1°, and 38.8°.
  • the peaks described above for crystalline Hydrate 3 have a relative intensity of at least 10%, of at least 15%, of at least 20%, or of at least 25%.
  • crystalline Hydrate 3 of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)- lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has an XRPD pattern that is substantially the same XRPD pattern shown in FIG. 14B.
  • crystalline Hydrate 3 of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)- lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has an XRPD pattern that substantially includes the peaks in Table 5B.
  • crystalline Hydrate 3 of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has a DSC pattern that is substantially the same DSC pattern shown in FIG. 15.
  • crystalline Hydrate 3 is characterized by an endotherm at 64° ⁇ 2° C, and a melt at 195° C ⁇ 2° C.
  • crystalline Hydrate 3 of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has a TGA pattern that is substantially the same TGA pattern shown in FIG. 16.
  • the crystalline Hydrate 3 of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)- lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine is characterized by at least three, at least four, or by at least five, x-ray powder diffraction peaks at 2Q angles selected from 10.3°, 12.1°, 13.5°, 16.9°, and 24.4°; optionally together with one or both of the TGA, and DSC
  • crystalline Hydrate 3 is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten x-ray powder diffraction peaks at 2Q angles selected from 10.3°, 12.1°, 13.5°, 15.9°, 16.9°, 17.6°, 22.0°, 22.9°, 24.4°, and 28.9° optionally together with one or both of the TGA, and DSC parameters recited above for Hydrate 3.
  • the crystalline Hydrate 3 of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)- lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine is characterized by at least three, at least four, or by at least five, x-ray powder diffraction peaks at 2Q angles selected from 10.5°, 13.9°, 15.0°, 16.5°, 17.2°, and 17.6°, optionally together with one or both of the TGA, and DSC parameters recited above for Hydrate 3.
  • crystalline Hydrate 3 is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten x-ray powder diffraction peaks at 2Q angles selected from 10.5°, 13.9°, 15.0°, 16.5°, 17.2°, 17.6°, 18.3°, 19.1°, 20.3°, 23.7°, and 30.1°, optionally together with one or both of the TGA, and DSC parameters recited above for Hydrate 3.
  • the crystalline Hydrate 3 of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)- lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine is characterized by at least three, at least four, or by at least five, x-ray powder diffraction peaks at 2Q angles selected from at least three, or at least four x-ray powder diffraction peaks at 2Q angles selected from 10.3°, 12.1°, 17.6°, and 22.0°, optionally together with one or both of the TGA, and DSC parameters recited above for Hydrate 3.
  • crystalline ethanol solvate of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)- lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine is characterized by x-ray powder diffraction pattern.
  • the x-ray powder diffraction pattern can be acquired at room temperature in reflection mode using a Bruker D8 Discover system described herein.
  • crystalline ethanol solvate is characterized by at least three, at least four, at least five, at least six, or at least seven x-ray powder diffraction peaks at 2Q angles selected from 10.4°, 13.8°, 17.1°, 17.5°, 20.2°, 25.5°, and 30.0°.
  • the peaks described above for crystalline ethanol solvate have a relative intensity of at least 10%, of at least 15%, of at least 20%, or of at least 25%.
  • crystalline ethanol solvate of 8-(2-fluorobenzyl)-6-(3- (trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has an XRPD pattern that is substantially the same XRPD pattern shown in FIG. 17.
  • crystalline ethanol solvate of 8-(2-fluorobenzyl)-6-(3- (trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has an XRPD pattern that substantially includes the peaks in Table 6.
  • crystalline ethanol solvate of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)- lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has a TGA pattern that is substantially the same TGA pattern shown in FIG. 18.
  • the crystalline ethanol solvate of 8-(2-fluorobenzyl)-6-(3- (trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine is characterized by at least three, at least four, by at least five, at least six, or at least seven x-ray powder diffraction peaks at 2Q angles selected from 10.4°, 13.8°, 17.1°, 17.5°, 20.2°, 25.5°, and 30.0°; together with the TGA parameters recited above for ethanol solvate.
  • crystalline methanol solvate of 8-(2-fluorobenzyl)-6-(3- (trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine is characterized by x-ray powder diffraction pattern.
  • the x-ray powder diffraction pattern can be acquired at room temperature in reflection mode using a Bruker D8 Discover system described herein.
  • crystalline methanol solvate is characterized by at least three, at least four, at least five, at least six, at least seven or at least eight x-ray powder diffraction peaks at 2Q angles selected from 7.7°, 11.0°, 14.2°, 16.2°, 17.1°, 23.0°, and 24.2°.
  • the peaks described above for crystalline methanol solvate have a relative intensity of at least 10%, of at least 15%, of at least 20%, or of at least 25%.
  • crystalline methanol solvate of 8-(2-fluorobenzyl)-6-(3- (trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has an XRPD pattern that is substantially the same XRPD pattern shown in FIG. 19.
  • crystalline methanol solvate of 8-(2-fluorobenzyl)-6-(3- (trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has an XRPD pattern that substantially includes the peaks in Table 7.
  • crystalline methanol solvate of 8-(2-fluorobenzyl)-6-(3- (trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has a TGA pattern that is substantially the same TGA pattern shown in FIG. 20.
  • the crystalline methanol solvate of 8-(2-fluorobenzyl)-6-(3- (trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine is characterized by at least three, at least four, by at least five, at least six, at least seven, or at least eight x-ray powder diffraction peaks at 2Q angles selected from 7.7°, 13.8°, 11.0°, 14.2°, 16.2°, 17.1°, 23.0°, and 24.2°; together with the TGA parameters recited above for methanol solvate.
  • crystalline methyl ethyl ketone solvate of 8-(2-fluorobenzyl)-6-(3- (trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine is characterized by x-ray powder diffraction pattern.
  • the x-ray powder diffraction pattern can be acquired at room temperature in reflection mode using a Bruker D8 Discover system described herein.
  • crystalline methyl ethyl ketone solvate is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine or at least ten x-ray powder diffraction peaks at 2Q angles selected from 13.7°, 17.3°, 17.8°, 18.4°, 21.1°, 22.8°, 24.0°, 24.3°, and 25.1°.
  • the peaks described above for crystalline methyl ethyl ketone solvate have a relative intensity of at least 10%, of at least 15%, of at least 20%, or of at least 25%.
  • crystalline methyl ethyl ketone solvate of 8-(2-fluorobenzyl)-6-(3- (trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has an XRPD pattern that is substantially the same XRPD pattern shown in FIG. 21.
  • crystalline methyl ethyl ketone solvate of 8-(2-fluorobenzyl)-6-(3- (trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has an XRPD pattern that substantially includes the peaks in Table 8.
  • crystalline dichloromethane solvate of 8-(2-fluorobenzyl)-6-(3- (trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine is characterized by x-ray powder diffraction pattern.
  • the x-ray powder diffraction pattern can be acquired at room temperature in reflection mode using a Bruker D8 Discover system described herein.
  • crystalline dichloromethane solvate is characterized by at least three, at least four, at least five, at least six, or at least seven x-ray powder diffraction peaks at 2Q angles selected from 14.4°, 15.7°, 19.7°, 20.9°, 21.8°, 22.7°, and 24.0°.
  • the peaks described above for crystalline dichloromethane solvate have a relative intensity of at least 10%, of at least 15%, of at least 20%, or of at least 25%.
  • crystalline dichloromethane solvate of 8-(2-fluorobenzyl)-6-(3- (trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has an XRPD pattern that is substantially the same XRPD pattern shown in FIG. 22.
  • crystalline dichloromethane solvate of 8-(2-fluorobenzyl)-6-(3- (trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has an XRPD pattern that substantially includes the peaks in Table 9.
  • crystalline dichloromethane solvate of 8-(2-fluorobenzyl)-6-(3- (trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has a TGA pattern that is substantially the same TGA pattern shown in FIG. 23.
  • the crystalline dichloromethane solvate of 8-(2-fluorobenzyl)-6-(3- (trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine is characterized by at least three, at least four, by at least five, at least six, at least seven, or at least eight x-ray powder diffraction peaks at 2Q angles selected from 14.4°, 15.7°, 19.7°, 20.9°, 21.8°, 22.7°, and 24.0°; together with the TGA parameters recited above for dichloromethane solvate.
  • crystalline acetonitrile solvate of 8-(2-fluorobenzyl)-6-(3- (trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine is characterized by x-ray powder diffraction pattern.
  • the x-ray powder diffraction pattern can be acquired at room temperature in reflection mode using a Bruker D8 Discover system described herein.
  • crystalline acetonitrile solvate is characterized by at least three, at least four, at least five, at least six, or at least seven x-ray powder diffraction peaks at 2Q angles selected from 10.6°, 14.4°, 17.3°, 18.7°, 21.7°, 25.3°, and 25.9°.
  • the peaks described above for crystalline acetonitrile solvate have a relative intensity of at least 10%, of at least 15%, of at least 20%, or of at least 25%.
  • crystalline acetonitrile solvate of 8-(2-fluorobenzyl)-6-(3- (trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has an XRPD pattern that is substantially the same XRPD pattern shown in FIG. 24.
  • crystalline acetonitrile solvate of 8-(2-fluorobenzyl)-6-(3- (trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has an XRPD pattern that substantially includes the peaks in Table 10.
  • crystalline acetonitrile solvate of 8-(2-fluorobenzyl)-6-(3- (trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine has a TGA pattern that is substantially the same TGA pattern shown in FIG. 25.
  • the crystalline acetonitrile solvate of 8-(2-fluorobenzyl)-6-(3- (trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine is characterized by at least three, at least four, by at least five, at least six, at least seven, or at least eight x-ray powder diffraction peaks at 2Q angles selected from 10.6°, 14.4°, 17.3°, 18.7°, 21.7°, 25.3°, and 25.9°; together with the TGA parameters recited above for acetonitrile solvate.
  • 2-theta values of the X-ray powder diffraction patterns for crystalline Form A, Form B, Hydrate 1, Hydrate 2, Hydrate 3, ethanol solvate, methanol solvate, methyl ethyl ketone solvate, dichloromethane solvate, or acetonitrile solvate may vary slightly from one instrument to another and depending on variations in sample preparation and batch to batch variation.
  • the XRPD peak positions for crystalline Form A, Form B, Hydrate 1, Hydrate 2, Hydrate 3, ethanol solvate, methanol solvate, methyl ethyl ketone solvate, dichloromethane solvate, or acetonitrile solvate are not to be construed as absolute and can vary ⁇ 0.2 degrees.
  • FIG. 8A” and“substantially the same XRPD pattern as shown in FIG. 8B” and“substantially the same XRPD pattern as shown in FIG. 11 A” and“substantially the same XRPD pattern as shown in FIG. 11B” and “substantially the same XRPD pattern as shown in FIG. 14 A” and“substantially the same XRPD pattern as shown in FIG. 14B” means that for comparison purposes, at least 90% of the peaks shown in FIG. 1A, FIG. 1B, FIG. 5A, FIG. 5B, FIG. 8A, FIG. 8B, FIG. 11 A, FIG.
  • FIG. 14A and FIG. 14B are present. It is to be further understood that for comparison purposes some variability in peak position from those shown in FIG. 1 A, FIG. 1B FIG. 5 A, FIG. 5B, FIG. 8A, FIG. 8B, FIG. 11 A, FIG. 11B, FIG. 14A and FIG. 14B are allowed, such as+0.2 degrees.
  • substantially the same XRPD pattern as shown in FIG. 17 (or FIG. 19 or FIG. 21 or FIG. 22 or FIG. 24 or FIG. 26)” means that for comparison purposes, at least 90% of the peaks shown in FIG. 17 (or FIG. 19, FIG. 21, FIG. 22, FIG. 24, or FIG. 26) are present. It is to be further understood that for comparison purposes some variability in peak position from those shown in FIG. 17, FIG. 19, FIG. 21, FIG. 22, FIG. 24, FIG. 26 are allowed, such as+0.2 degrees.
  • the present disclosure provides a process for preparing crystalline Form A of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)- 1 H- 1 ,2,4-triazol-5-yl)imidazo[ 1 ,2-a]pyrazine.
  • Such a process includes, e.g., forming crystalline Form A from a mixture comprising 8-(2- fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine, isopropyl acetate (IP AC) and n-heptane, where the n-heptane makes up more than 50% by volume of the composition.
  • IP AC isopropyl acetate
  • the process comprises stirring the mixture comprising 8-(2- fluorobenzyl)-6-(3-(trifluoromethyl)- 1H- 1 ,2,4-triazol-5-yl)imidazo[ 1 ,2-a]pyrazine and IP AC and n-heptane, where the n-heptane makes up more than 50% by volume of the composition for 24 hours to 1 week at room temperature.
  • the processes described above results in the formation of crystalline Form A.
  • the present disclosure provides a process for preparing crystalline Form A of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)- 1 H- 1 ,2,4-triazol-5-yl)imidazo[ 1 ,2-a]pyrazine.
  • a process includes, e.g., forming crystalline Form A from a mixture comprising 8-(2- fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine and 100% n-heptane or cyclohexane.
  • the process comprises stirring the mixture comprising 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2- a]pyrazine and 100% n-heptane or cyclohexane for 24 hours to 1 week at room temperature.
  • the processes described above results in the formation of crystalline Form A.
  • the present disclosure provides a process for preparing crystalline Form A of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)- 1 H- 1 ,2,4-triazol-5-yl)imidazo[ 1 ,2-a]pyrazine.
  • Such a process includes, e.g., forming crystalline Form A from a mixture comprising 8-(2- fluorobenzyl)-6-(3-(trifluoromethyl)- 1H- 1 ,2,4-triazol-5-yl)imidazo[ 1 ,2-a]pyrazine and isopropyl acetate and heating the mixture to 45°, immediately diluting the suspension with n- heptane and stirred for 2 hours while slowly cooling to 20°, and then stirring for another 2 hours to 5°.
  • the processes described above results in the formation of crystalline Form A.
  • the present disclosure provides a process for preparing crystalline Form B of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine.
  • a process includes, e.g., forming crystalline Form B from a mixture comprising 8-(2- fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine Form A and a solvent selected from (i) isopropyl acetate (IP AC), (ii) isopropyl alcohol (IPA); (iii)
  • IP A/IP AC mixtures (iv) mixtures of IP AC and hexane with IP AC making up 50% or more by volume of the composition, and (v) tetrahydrofuran.
  • the process comprises stirring the mixture comprising 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5- yl)imidazo[l,2-a]pyrazine Form A and in a solvent selected from isopropyl acetate (IP AC), isopropyl alcohol (IPA); IP A/IP AC mixtures; mixtures of IP AC and hexane with IP AC making up 50% or more by volume of the composition, and tetrahydrofuran for 24 hours to 1 week at room temperature.
  • the processes described above results in the formation of crystalline Form B.
  • the present disclosure provides a process for preparing crystalline Hydrate 1 of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2- a]pyrazine.
  • a process includes, e.g., forming crystalline Hydrate 1 from a mixture comprising 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2- a]pyrazine Form A or Form B and water.
  • the process comprises stirring the mixture comprising 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5- yl)imidazo[l,2-a]pyrazine Form A or Form B and water for 24 hours to 1 week at room temperature.
  • the processes described above results in the formation of crystalline Hydrate 1.
  • the present disclosure provides a process for preparing crystalline Hydrate 2 of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2- a]pyrazine.
  • Such a process includes, e.g., forming crystalline Hydrate 1 from a mixture comprising 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2- a]pyrazine Form A or Form B and an aqueous mixture containing cellulose-based polymers such as methylcellulose, surfactants such as Tween 80 and sodium lauryl sulfate, or a combination thereof; or forming crystalline Hydrate 1 from a mixture comprising 8-(2- fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine Form A or Form B and an aqueous mixture containing 10% of organic solvents such as isopropyl alcohol.
  • the process comprises stirring the mixture comprising 8-(2- fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine Form A or Form B and an aqueous mixture containing cellulose-based polymers such as
  • methylcellulose methylcellulose, surfactants such as Tween 80 and sodium lauryl sulfate, or a combination thereof; or the mixture comprising 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- 1,2,4- triazol-5-yl)imidazo[l,2-a]pyrazine Form A or Form B and an aqueous mixture containing 10% of organic solvents such as isopropyl alcohol for 24 hours to 1 week at room
  • the present disclosure provides a process for preparing crystalline Hydrate 3 of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2- a]pyrazine.
  • a process includes, e.g., forming crystalline Hydrate 3 from a mixture comprising 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2- a]pyrazine Form A or Form B and a solvent mixture containing 50% water and 50% organic solvent such as isopropyl alcohol.
  • the process comprises stirring the mixture comprising 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2- a]pyrazine Form A or Form B and a solvent mixture containing 50% water and 50% organic solvent such as isopropyl alcohol for 24 hours to 1 week at room temperature.
  • a solvent mixture containing 50% water and 50% organic solvent such as isopropyl alcohol for 24 hours to 1 week at room temperature.
  • the present disclosure provides a process for preparing crystalline ethanol solvate of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5- yl)imidazo[l,2-a]pyrazine.
  • a process includes, e.g., forming crystalline ethanol solvate from a mixture comprising 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5- yl)imidazo[l,2-a]pyrazine Form A or Form B and 100% ethanol.
  • the process comprises stirring the mixture comprising 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine Form A or Form B and ethanol for 24 hours to 1 week at room temperature.
  • the processes described above results in the formation of crystalline ethanol solvate.
  • the present disclosure provides a process for preparing crystalline methanol solvate of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5- yl)imidazo[l,2-a]pyrazine.
  • a process includes, e.g., forming crystalline methanol solvate from a mixture comprising 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4- triazol-5-yl)imidazo[l,2-a]pyrazine Form A or Form B and 100% methanol.
  • the process comprises stirring the mixture comprising 8-(2-fluorobenzyl)-6-(3- (trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine Form A or Form B and methanol for 24 hours to 1 week at room temperature.
  • the processes described above results in the formation of crystalline methanol solvate.
  • the present disclosure provides a process for preparing crystalline methyl ethyl ketone solvate of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5- yl)imidazo[l,2-a]pyrazine.
  • a process includes, e.g., forming crystalline methyl ethyl ketone solvate from a mixture comprising 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine Form A or Form B and 100% methyl ethyl ketone.
  • the process comprises stirring the mixture comprising 8-(2-fluorobenzyl)-6-(3- (trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine Form A or Form B and methyl ethyl ketone for 24 hours to 1 week at room temperature.
  • the processes described above results in the formation of crystalline methyl ethyl ketone solvate.
  • the present disclosure provides a process for preparing crystalline dichloromethane solvate of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5- yl)imidazo[l,2-a]pyrazine.
  • a process includes, e.g., forming crystalline dichloromethane solvate from a mixture comprising 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4- triazol-5-yl)imidazo[l,2-a]pyrazine Form A or Form B and 100% dichloromethane.
  • the process comprises stirring the mixture comprising 8-(2-fluorobenzyl)-6-(3- (trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine Form A or Form B and dichloromethane for 24 hours to 1 week at room temperature.
  • the processes described above results in the formation of crystalline dichloromethane solvate.
  • the present disclosure provides a process for preparing crystalline acetonitrile solvate of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5- yl)imidazo[l,2-a]pyrazine.
  • a process includes, e.g., forming crystalline acetonitrile solvate from a mixture comprising 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4- triazol-5-yl)imidazo[l,2-a]pyrazine Form A or Form B and 100% acetonitrile.
  • the process comprises stirring the mixture comprising 8-(2-fluorobenzyl)-6-(3- (trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine Form A or Form B and in acetonitrile for 24 hours to 1 week at room temperature.
  • the processes described above results in the formation of crystalline acetonitrile solvate.
  • polymorphic forms disclosed herein may be formulated as pharmaceutical compositions or“formulations”.
  • a typical formulation is prepared by mixing Form A, Form B, Hydrate 1, Hydrate 2, Hydrate 3, ethanol solvate, methanol solvate, methyl ethyl ketone solvate, dichloromethane solvate, or acetonitrile solvate of the compound of Formula (I) and a carrier, diluent or excipient.
  • Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
  • Solvents are generally selected based on solvents recognized by persons skilled in the art as safe (GRAS-Generally Regarded as Safe) to be administered to a mammal.
  • safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water.
  • Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300), etc. and mixtures thereof.
  • the formulations may also include other types of excipients such as one or more buffers, stabilizing agents, antiadherents, surfactants, wetting agents, lubricating agents, emulsifiers, binders, suspending agents, disintegrants, fillers, sorbents, coatings (e.g. enteric or slow release) preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e ., a compound of Formula I or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
  • excipients such as one or more buffers, stabilizing agents, antiadherents, surfactants, wetting agents, lubricating agents, emulsifiers, binders, suspending agents, disintegrants, fillers, sorbents, coatings (e.g. enteric or slow release)
  • Acceptable diluents, carriers, excipients, and stabilizers are those that are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol;
  • buffers such as phosphate, citrate, and other organic acids
  • antioxidants including ascorbic acid and methionine
  • preservatives such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride;
  • proteins such as serum albumin, gelatin, or immunoglobulins
  • hydrophilic polymers such as polyvinylpyrrolidone
  • amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine
  • chelating agents such as EDTA
  • sugars such as sucrose, mannitol, trehalose or sorbitol
  • salt-forming counter-ions such as sodium
  • metal complexes e.g.
  • the active pharmaceutical ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, e.g., hydroxymethylcellulose or gelatin- microcapsules and poly-(methylmethacylate) microcapsules, respectively; in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano particles and nanocapsules) or in macroemulsions.
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano particles and nanocapsules
  • Remington's The Science and Practice of Pharmacy, 2l st Edition, University of the Sciences in Philadelphia, Eds., 2005 (hereafter“Remington’s”).
  • the formulations may be prepared using conventional dissolution and mixing procedures.
  • therapeutically effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • the therapeutically effective amount of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to ameliorate, cure or treat the disease, or one or more of its symptoms.
  • “administer”,“administering” or“administration” in reference to a compound, composition or dosage form of the invention means introducing the compound into the system of the subject or patient in need of treatment.
  • “administration” and its variants are each understood to include concurrent and/or sequential introduction of the compound and the other active agents.
  • compositions described herein may be administered systemically or locally, e.g. orally (including, but not limited to solid dosage forms including hard or soft capsules (e.g. gelatin capsules), tablets, pills, powders, sublingual tablets, troches, lozenges, and granules; and liquid dosage forms including, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, aqueous or oil solutions, suspensions, syrups and elixirs, by inhalation (e.g. with an aerosol, gas, inhaler, nebulizer or the like), to the ear (e.g. using ear drops), topically (e.g.
  • ophthalmically e.g. with eye drops, ophthalmic gels, ophthalmic ointments
  • rectally e.g. using enemas or suppositories
  • nasally, buccally, vaginally e.g. using douches, intrauterine devices, vaginal suppositories, vaginal rings or tablets, etc.
  • vaginally e.g. using douches, intrauterine devices, vaginal suppositories, vaginal rings or tablets, etc.
  • ear drops via an implanted reservoir or the like, or parenterally depending on the severity and type of the disease being treated.
  • parenteral includes, but is not limited to, subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • Formulations of a compound intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i
  • Tablets may be uncoated or may be coated by known techniques including microencapsulation to mask an unpleasant taste or to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl
  • a water soluble taste masking material such as hydroxypropyl-methylcellulose or hydroxypropyl-cellulose may be employed.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 -butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • the oral compositions can also include excipients and adjuvants such as dispersing or wetting agents, such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived
  • polyoxyethylene sorbitan monooleate polyoxyethylene sorbitan monooleate
  • emulsifying and suspending agents such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia
  • sweetening, flavoring, and perfuming agents and/or one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.
  • compositions may also be administered by nasal aerosol or by inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • Formulations suitable for intrapulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 micros (including particles in a range between 0.1 and 500 microns in increments microns such as 0.5, 1, 30, 35 microns, etc.) which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs.
  • compositions described herein may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the ear, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2 octyldodecanol, benzyl alcohol and water.
  • the active ingredients may be formulated in a cream with an oil-in- water cream base.
  • the aqueous phase of the cream base may include a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane l,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof.
  • the topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulfoxide and related analogs.
  • the oily phase of emulsions prepared using a compound of Formula I may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. A hydrophilic emulsifier may be included together with a lipophilic emulsifier which acts as a stabilizer. In some embodiments, the emulsifier includes both an oil and a fat.
  • Emulgents and emulsion stabilizers suitable for use in the formulation of a compound of Formula I include TweenTM-60, SpanTM-80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.
  • transdermal patches which have the added advantage of providing controlled delivery of a compound to the body.
  • dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as
  • compositions may be formulated in an ointment such as petrolatum.
  • an ointment such as petrolatum
  • the formulations may be applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w.
  • the active ingredients may be employed with either an oil-based, paraffinic or a water-miscible ointment base.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds described herein with suitable non-irritating excipients or carriers such as cocoa butter, beeswax, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, beeswax, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, beeswax, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Other formulations suitable for vaginal administration may be presented as pess
  • Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents (including those described in the preceding paragraph).
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non toxic parenterally-acceptable diluent or solvent, for example as a solution in l,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are examples of the oils.
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides.
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, especially in their polyoxyethylated versions, or in mineral oil such as liquid paraffin.
  • oils such as a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, especially in their polyoxyethylated versions, or in mineral oil such as liquid paraffin.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • compositions may be preserved by the addition of an anti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.
  • Form A, Form B, Hydrate 1, Hydrate 2, Hydrate 3, ethanol solvate, methanol solvate, methyl ethyl ketone solvate, dichloromethane solvate, or acetonitrile solvate of the compound of Formula (I) may be formulated in a veterinary composition comprising a veterinary carrier.
  • Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert. In the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route.
  • the invention also provides a method of treating a disease in a subject in need thereof, comprising administering, alone or in combination therapy, a therapeutically effective amount of Form A, Form B, Hydrate 1, Hydrate 2, Hydrate 3, ethanol solvate, methanol solvate, methyl ethyl ketone solvate, dichloromethane solvate, or acetonitrile solvate of the compound of Formula (I) to the subject; wherein the disease is one that benefits from sGC stimulation or from an increase in the concentration of NO or cGMP or both, or from the upregulation of the NO pathway.
  • the invention also provides a method of treating a disease in a subject in need thereof, comprising administering, alone or in combination therapy, a pharmaceutical composition comprising Form A, Form B, Hydrate 1, Hydrate 2, Hydrate 3, ethanol solvate, methanol solvate, methyl ethyl ketone solvate, dichloromethane solvate, or acetonitrile solvate to the
  • the compounds here disclosed are sGC stimulators that may be useful in the prevention and/or treatment of diseases characterized by undesirable reduced bioavailability of and/or sensitivity to NO, such as those associated with conditions of oxidative stress or nitrosative stress.
  • sGC stimulators may be used to treat and/or prevent a range of diseases.
  • administering an sGC stimulator of the invention e.g ., Form A, Form B, Hydrate 1, Hydrate 2, Hydrate 3, ethanol solvate, methanol solvate, methyl ethyl ketone solvate, dichloromethane solvate, or acetonitrile solvate
  • an sGC stimulator of the invention e.g ., Form A, Form B, Hydrate 1, Hydrate 2, Hydrate 3, ethanol solvate, methanol solvate, methyl ethyl ketone solvate, dichloromethane solvate, or acetonitrile solvate
  • osteoclastic bone remodeling following osteoclastic bone remodeling, osteoclastic bone resorption, new bone formation
  • brain aneurism brain hypoxia, cancer metastasis, cerebral amyloid angiopathy (CAA) or congophilic angiopathy, cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy
  • CAA cerebral amyloid angiopathy
  • congophilic angiopathy cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy
  • CADASIL cerebral perfusion
  • cerebral small vessel disease cerebral vasospasm
  • chemo-brain childhood disintegrative disorder
  • chronic bronchitis chronic fatigue
  • chronic traumatic encephalopathy CTE
  • ciliopathies cirrhosis (e.g., liver cirrhosis, liver cirrhosis associated with chronic liver disease, primary biliary cirrhosis), CNS-disease related sexual dysfunction, CNS-disease related sleep disturbances, cognitive defect associated with Huntington's Disease, cognitive dysfunction, cognitive impairment (e.g., vascular cognitive impairment, mild cognitive impairment, cognitive impairment associated with diabetes, cognitive impairment associated with Multiple Sclerosis, cognitive impairment associated with obstructive sleep apnea, cognitive impairment associated with schizophrenia (CIAS), cognitive impairment associated with sickle cell disease, concussion, congenital myasthenic syndrome, connective tissue disease, consequences of cerebral infarction (apoplexia cerebri), conservation of blood substituents in trauma patients, CREST syndrome
  • HIV-associated dementia including asymptomatic neurocognitive impairment (ANI), minor neurocognitive disorder (MND), HIV-associated dementia (HAD, also called AIDS dementia complex [ADC] or HIV encephalopathy), pre-senile dementia (mild cognitive impairment, MCI), mixed dementia, Binswanger's dementia (subcortical arteriosclerotic encephalopathy), Parkinson's Dementia), demyelination, depression, depressive disorder, dermatomyositis, diabetic angiopathy, diabetic macular edema, diabetic microangiopathies, diabetic ulcers or wounds (e.g., diabetic food ulcer), diseases associated with or related to metabolic syndrome (e.g.
  • obesity obesity, diabetes, insulin resistance, elevated fasting glucose, elevated fasting insulin, elevated lipids
  • diseases involving downregulated neurotransmitters diseases involving impaired cerebral blood flow, diseases involving impaired neurodegeneration, diseases involving impaired synaptic function, diseases involving neuroinflammation, diseases involving neurotoxicity, diseases of the organs of the male and female urogenital system (benign and malignant), disturbances of concentration in children with learning and memory problems, Down syndrome, drug addiction, drug-induced psychosis, dry eye syndrome, Duchenne muscular dystrophy, Dupuytren’s contracture, dyskinesia (e.g., acute dyskinesia, chronic or tardive dyskinesia, non-motor dyskinesia, levo-dopa induced dyskinesia (LID)), dysmenhorrea (e.g., primary dysmenhorrea, secondary dysmenhorrea), dyspaneuria, dysphagia, dystonia (e.g., generalized dystonia, focal dystonia,
  • osteomyelofibrosis functional dyspepsia, gastroparesis, Gaucher Disease, general disturbances of concentration, general psychosis, glaucoma, glioblastoma, glomerulopathies (e.g., glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, focal segmental glomerulosclerosis), granulomas, head injury, hearing impairment (e.g., partial hearing loss, total hearing loss, partial deafness, total deafness, noise-induced hearing loss), heart disease (e.g., left ventricular myocardial remodeling, left ventricular systolic dysfunction, ischemic cardiomyopathy, dilatated cardiomyopathy, alcoholic cardiomyopathy, storage cardiomyopathies, congenital heart deffects, decreased coronary blood flow, diastolic or systolic dysfunction, coronary insuffici
  • tachyarrhythmia torsade-de-pointes tachycardia, atrial and ventricular extrasystoles, AV- junction extrasystoles, sick-sinus syndrome, AV-node reentry tachycardia, Wolff-Parkinson- White syndrome, myocardial insufficiency, chronic, acute or viral myocarditis, cardiogenic shock, cardiac remodeling), heart failure (HF; e.g.: Heart failure with preserved ejection fraction (HFPEF), Heart failure with reduced ejection fraction (HFREF), acute heart failure, chronic heart failure, acute phases of an existing chronic heart failure (worsening HF), transient heart failure, post-acute heart failure, systolic heart failure, diastolic heart failure, congestive heart failure, acute decompensated heart failure, right ventricular failure, total heart failure, high output heart failure, heart failure with valvular defects, diabetic heart failure, heart failure/cardiorenal syndrome, right heart
  • renal-insufficiency related to pulmonary enema renal-insufficiency related to HF
  • renal-insufficiency related to uremia or anemia primary kidney disease, congenital kidney disease, polycystic kidney disease progression, kidney transplant rejection, immune complex-induced kidney disease, abnormally reduced creatinine and/or water excretion, abnormally increased blood concentrations of urea, nitrogen, potassium and/or creatinine, altered activity of renal enzymes (e.g.
  • glutamyl synthetase altered urine osmolarity or urine volume, increased microalbuminuria, macroalbuminuria, lesions of glomeruli and arterioles, tubular dilatation, hyperphosphatemia, vascular kidney disease, renal cysts, renal edema due to HF), Korsakoff psychosis, leukocyte activation, levo-dopa induced addictive behavior, lichen sclerosus, lipid related disorders (e.g., excessive adiposity, excessive subcutaneous fat, hyperlipidemias, dyslipidemia, hypercholesterolemias, decreased high-density lipoprotein cholesterol (HDL-cholesterol), moderately elevated low-density lipoprotein cholesterol (LDL-cholesterol) levels, hypertriglyceridemias, hyperglyceridemia, hypolipoproteinanemias, sitosterolemia, fatty liver disease, liver steatosis or abnormal lipid accumulation in the liver, steatosis of the heart, kidney or muscle,
  • cholestatic liver disease associated with granulomatous liver diseases cholestatic liver disease associated with liver malignancies, cholestatic liver disease associated with intrahepatic cholestasis of pregnancy, cholestatic liver disease associated with hepatitis, cholestatic liver disease associated with sepsis, cholestatic liver disease associated with drugs or toxins, cholestatic liver disease associated with graft-versus-host disease, cholestatic liver disease associated with post-liver transplantation, cholestatic liver disease associated with choledocholithiasis, cholestatic liver disease associated with bile duct tumors, cholestatic liver disease associated with pancreatic carcinoma, cholestatic liver disease associated with Mirizzi’s syndrome, cholestatic liver disease associated with AIDS, cholangiopathy, cholestatic liver disease associated with parasites, cholestatic liver disease associated with schistosomiasis, hepatitis, non-alcoholic steatohepatitis (NASH), non-alcoholic
  • neuropathy non-painful diabetic neuropathy, neuropathies associated to a CNS disease (e.g., Multiple sclerosis, MS), radiation-induced neuropathy), neuropathic pain associated with shingles, neuropathic pain associated with spine surgery), obsessive compulsive disorder (OCD), obstructive thromboanginitis, obstructive uropathy, oesinophilic fasciitis,
  • CNS disease e.g., Multiple sclerosis, MS
  • radiation-induced neuropathy neuropathic pain associated with shingles, neuropathic pain associated with spine surgery
  • OCD obsessive compulsive disorder
  • obstructive thromboanginitis obstructive uropathy
  • oesinophilic fasciitis oesinophilic fasciitis
  • osteoporosis overactive bladder
  • pain e.g., acute pain, central pain syndrome, inflammatory pain, post-operative pain, tonic pain, visceral pain, claudication pain, orphan pain indications (e.g., Acetazolamide-responsive myotonia, Autoerythrocyte sensitization syndrome,
  • Autosomal dominant Charcot-Marie-Tooth disease type 2V Autosomal dominant intermediate Charcot-Marie-Tooth disease with neuropathic pain
  • Autosomal recessive limb- girdle muscular dystrophy type 2A Autosomal recessive limb- girdle muscular dystrophy type 2A, Channelopathy-associated congenital insensitivity to pain, Chronic pain requiring intraspinal analgesia, Complex regional pain syndrome,
  • Complex regional pain syndrome type 1 Complex regional pain syndrome type 2, Congenital insensitivity to pain with hyperhidrosis, Congenital insensitivity to pain with severe intellectual disability, Congenital insensitivity to pain-hypohidrosis syndrome, Diffuse palmoplantar keratoderma with painful fissures, Familial episodic pain syndrome, Familial episodic pain syndrome with predominantly lower limb involvement, Familial episodic pain syndrome with predominantly upper body involvement, Hereditary painful callosities, Hereditary sensory and autonomic neuropathy type 4, Hereditary sensory and autonomic neuropathy type 5, Hereditary sensory and autonomic neuropathy type 7, Interstitial cystitis, Painful orbital and systemic neurofibromas-marfanoid habitus syndrome, Paroxysmal extreme pain disorder, Persistent idiopathic facial pain, Qualitative or quantitative defects of calpain, Tolosa-Hunt syndrome, pancreatitis, panic disorder, Parkinson’s disease,
  • Parkinsonism Plus Parkinson's Dysphagia, pathological eating disorders, pelvic pain
  • peripheral vascular disease e.g., peripheral arterial disease, peripheral arterial occlusive disease, peripheral embolism, peripheral perfusion disturbances
  • peritonitis pervasive development disorder
  • Peyronie’s disease Picks syndrome, polychondritis, polymyositis, post herpetic neuralgia, post-traumatic head injury, post-traumatic stress disorder (PTSD), premature ejaculation, progressive nuclear palsy, prostate hypertrophy
  • pulmonary disease e.g., plexogenic pulmonary arteriopathy, bronchoconstriction or pulmonary
  • pulmonary disease of the lung chronic obstructive pulmonary disease (COPD), pulmonary capillary hemangiomatosis, lymphangiomatosis and compressed pulmonary vessels (e.g., due to adenopathy, tumor or fibrosing mediastinitis), pulmonary vascular remodeling, pulmonary hypertonia), pulmonary hypertension (PH, e.g., pulmonary arterial hypertension (PAH), primary PH, secondary PH, sporatid PH, pre-capically PH, idiopathic PH, PH associated with left ventricular disease, PH associated with HIV, PH associated with SCD, PH associated with thromoboembolism (chronic thromboembolic PH or CTEPH), PH associated with sarcoidosis, PH associated with chronic obstructive pulmonary disease, PH associated with acute respiratory distress syndrome (ARDS), PH associated with acute lung injury, PH associated with alpha- 1 -antitrypsin defici
  • COPD chronic o
  • PH associated with cystic fibrosis CF
  • PH associated with left ventricular dysfunction PH associated with hypoxemia
  • PH (WHO groups I, II, III, IV and V) PH associated with mitral valve disease
  • PH associated with pericarditis PH associated with constrictive pericarditis
  • PH associated with aortic stenosis PH associated with dilated cardiomyopathy
  • PH associated with hyperthrophic cardiomyopathy PH associated with restrictive cardiomyopathy
  • PH associated with mediastinal fibrosis PH associated with pulmonary fibrosis, PH associated with anomalous pulmonary venous drainage, PH associated with pulmonary veno-occlusive disease, PH associated with pulmonary vasculitis, PH associated with collagen vascular disease, PH associated with congenital heart disease, PH associated with pulmonary venous hypertension, PH associated with interstitial lung disease, PH associated with sleep-disordered breathing, PH associated with chronic air
  • renal sclerosis progressive sclerosis, liver sclerosis, primary sclerosing cholanginitis, sclerosis of the gastro-intestinal tract, hippocampal sclerosis, focal sclerosis, primary lateral sclerosis, osteosclerosis, otosclerosis, atherosclerosis, tuberous sclerosis, systemic sclerosis), sepsis or septic shock or anaphylactic shock, Sickle Cell Anemia, Sickle Cell Disease, Sjogren’s syndrome, sleep-wake disorders, Sneddon's syndrome, spasms (e.g., coronary spasms, vascular spasms, spasms of the peripheral arteries), spinal cord injury, spinal muscular atrophy, spinal subluxations, spinocerebellar ataxias, Steel-Richardson-Olszewski disease (progressive supranuclear palsy), stroke, subarachnoid hemorrhage, subcortical arteriosclerotic encephalopathy, syncopes, tau
  • Kawasaki disease arteritis, aortitis
  • vaso-occlusive crisis vaso-occlusive crisis
  • venus graft failure wet age-related macular degeneration and Williams syndrome.
  • the disease is selected from, for example, Alzheimer's disease (including pre- Alzheimer's disease, mild to moderate Alzheimer's disease and moderate to severe Alzheimer's disease), dementia (e.g., vascular dementia, post-stroke dementia, Lewy body dementia, dementia with frontal lobe degeneration, dementia with frontotemporal lobar degeneration, dementia with corticobasal degeneration, Creutzfeldt- Jakob dementia, HIV-dementia, multi-infarct dementia, post-operative dementia, strategic single-infarct dementia, HIV-associated dementia (including asymptomatic neurocognitive impairment (ANI), minor neurocognitive disorder (MND), HIV-associated dementia (HAD, also called AIDS dementia complex [ADC] or HIV encephalopathy), pre-senile dementia (mild cognitive impairment, MCI), mixed dementia, Binswanger's dementia (subcortical arteriosclerotic encephalopathy), Parkinson's Dementia); -chronic traumatic encephalopathy (C
  • disease refers to any deviation from or interruption of the normal structure or function of any body part, organ, or system that is manifested by a characteristic set of symptoms and signs and whose etiology, pathology, and prognosis may be known or unknown.
  • the term disease encompasses other related terms such as disorder and condition (or medical condition) as well as syndromes, which are defined as a combination of symptoms resulting from a single cause or so commonly occurring together as to constitute a distinct clinical picture.
  • the term disease refers to an sGC, cGMP and/or NO mediated medical or pathological disease.
  • the terms“subject” and“patient” are used interchangeably.
  • the terms“subject” and“patient” refer to an animal (e.g., a bird such as a chicken, quail or turkey, or a mammal), specifically a“mammal” including a non-primate (e.g., a cow, pig, horse, sheep, rabbit, guinea pig, rat, cat, dog, and mouse) and a primate (e.g., a monkey, chimpanzee and a human), and more specifically a human.
  • a non-primate e.g., a cow, pig, horse, sheep, rabbit, guinea pig, rat, cat, dog, and mouse
  • a primate e.g., a monkey, chimpanzee and a human
  • the subject is a non-human animal such as a farm animal (e.g., a horse, cow, pig or sheep), or a companion animal or pet (e.g., a dog, cat, mice, rats, hamsters, gerbils, guinea pig or rabbit). In some embodiments, the subject is a human.
  • a farm animal e.g., a horse, cow, pig or sheep
  • a companion animal or pet e.g., a dog, cat, mice, rats, hamsters, gerbils, guinea pig or rabbit.
  • the subject is a human.
  • the invention also provides a method for treating one of the above diseases in a subject, comprising administering a therapeutically effective amount of Form A, Form B, Hydrate 1, Hydrate 2, Hydrate 3, ethanol solvate, methanol solvate, methyl ethyl ketone solvate, dichloromethane solvate, or acetonitrile solvate to the subject in need of the treatment.
  • the invention provides the use of Form A, Form B, Hydrate 1, Hydrate 2, Hydrate 3, ethanol solvate, methanol solvate, methyl ethyl ketone solvate, dichloromethane solvate, or acetonitrile solvate in the treatment of one of these diseases in a subject in need of the treatment.
  • Form A is also included in the invention.
  • Form B is also included in the invention.
  • the invention further provides a method of making or manufacturing a medicament useful for treating one of these diseases comprising using Form A, Form B, Hydrate 1, Hydrate 2, Hydrate 3, ethanol solvate, methanol solvate, methyl ethyl ketone solvate, dichloromethane solvate, or acetonitrile solvate.
  • biological sample refers to an in vitro or ex vivo sample, and includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; blood, saliva, urine, faeces, semen, tears, lymphatic fluid, ocular fluid, vitreous humour, cerebrospinal fluid (CSF), or other body fluids or extracts thereof.
  • CSF cerebrospinal fluid
  • Treating”,“treating” or“treatment” with regard to a disease refers to alleviating or abrogating the cause and/or the effects of the disease.
  • the terms“treat”, “treatment” and“treating” refer to the reduction or amelioration of the progression, severity and/or duration of disease, or the amelioration of one or more symptoms of the disease (i.e., “managing” without“curing” the disease).
  • treatment and“treating” refer to the amelioration of at least one measurable physical parameter of a disease.
  • the terms“treat”,“treatment” and“treating” refer to the inhibition of the progression of a disease, either physically by, e.g., stabilization of a discernible symptom or physiologically by, e.g., stabilization of a physiological parameter, or both.
  • the compounds and pharmaceutical compositions described herein can be used alone or in combination therapy for the treatment of a disease mediated, regulated or influenced by sGC, cGMP and/or NO.
  • the invention provides a method of stimulating sGC activity in a biological sample, comprising contacting said biological sample with a compound or composition of the invention.
  • a sGC stimulator in a biological sample is useful for a variety of purposes known to one of skill in the art. Examples of such purposes include, without limitation, biological assays and biological specimen storage.
  • the terms“in combination” (as in the phrase“in combination therapy”) or“co-administration” can be used interchangeably to refer to the use of more than one therapy (e.g., one or more therapeutic agents).
  • the use of the terms does not restrict the order in which therapies (e.g., therapeutic agents) are administered to a subject.
  • the compounds and pharmaceutical compositions described herein can be used in combination therapy with one or more additional therapeutic agents.
  • the active agents may be administered separately or in conjunction.
  • the administration of one element may be prior to, concurrent to, or subsequent to the administration of the other agent.
  • a“therapeutically effective amount” of the compounds and pharmaceutical compositions described herein and of the other agent or agents will depend on the type of drug used. Suitable dosages are known for approved agents and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition(s) being treated and the amount of a compound described herein being used. In cases where no amount is expressly noted, an effective amount should be assumed.
  • co-administration or combination therapy encompasses administration of the first and second amounts of the compounds in an essentially
  • simultaneous manner such as in a single pharmaceutical composition, for example, capsule or tablet having a fixed ratio of first and second amounts, or in multiple, separate capsules or tablets for each.
  • co administration also encompasses use of each compound in a sequential manner in either order.
  • the period of time between each administration which can result in the desired therapeutic effect can range from minutes to hours and can be determined taking into account the properties of each compound such as potency, solubility, bioavailability, plasma half-life and kinetic profile.
  • therapeutic agent can be administered in any order within about 24 hours of each other, within about 16 hours of each other, within about 8 hours of each other, within about 4 hours of each other, within about 1 hour of each other or within about 30 minutes of each other.
  • Examples of other therapeutic agents that may be combined with Form A, Form B, Hydrate 1, Hydrate 2, Hydrate 3, ethanol solvate, methanol solvate, methyl ethyl ketone solvate, dichloromethane solvate, or acetonitrile solvate either administered separately or in the same pharmaceutical composition include, but are not limited to:
  • EDRF Endothelium-derived releasing factor
  • NO donors such as a nitrosothiol, a nitrite, a sydnonimine, a NONOate, a N- nitrosamine, a N-hydroxyl nitrosamine, a nitrosimine, nitrotyrosine, a diazetine dioxide, an oxatriazole 5-imine, an oxime, a hydroxylamine, a N-hydroxyguanidine, a hydroxyurea or a furoxan.
  • Some examples of these types of compounds include: glyceryl trinitrate (also known as GTN, nitroglycerin, nitroglycerine, and trinitrogylcerin), the nitrate ester of glycerol;
  • SNP sodium nitroprusside
  • SIN-l 3-morpholinosydnonimine
  • SNAP S-nitroso-N- acetylpenicillamine
  • DETA/NO diethylenetriamine/NO
  • NO donors include: the classic
  • nitrovasodilators such as organic nitrate and nitrite esters, including nitroglycerin, amyl nitrite, isosorbide dinitrate, isosorbide 5-mononitrate, and nicorandil; isosorbide (Dilatrate®- SR , Imdur® , Ismo® , Isordil® , Isordil®, Titradose® , Monoket®), 3- morpholinosydnonimine; linsidomine chlorohydrate (“SIN-l”); S-nitroso-N- acetylpenicillamine (“SNAP”); S-nitrosoglutathione (GSNO), sodium nitroprusside, S- nitrosoglutathione mono-ethyl-ester (GSNO-ester), 6-(2-hydroxy-l-methyl- n i t o s o h y d a zi n o ) - -
  • Nitric Oxide Synthase substrates for example, L- arginine, n- hydroxyguanidine based analogs, such as N[G]-hydroxy-L-arginine (NOHA), l-(3, 4- dimethoxy-2-chlorobenzylideneamino)-3-hydroxyguanidine, and PR5 (l-(3, 4-dimethoxy-2- chlorobenzylideneamino)-3-hydroxyguanidine); L-arginine derivatives (such as homo-Arg, homo-NOHA, N-tert-butyloxy- and N-(3-methyl-2-butenyl)oxy-L-arginine, canavanine, epsilon guanidine-carpoic acid, agmatine, hydroxyl-agmatine, and L-tyrosyl-L-arginine); N- alkyl-N’-hydroxyguanidines (such as N-cyclopropyl-N’-hydroxyguanidine and
  • NO independent heme-independent sGC activators including, but not limited to:
  • BAY 58-2667 (described in patent publication DE19943635); HMR-1766 (ataciguat sodium, described in patent publication W0200000285l);S 3448 (2-(4-chloro- phenylsulfonylamino)-4,5-dimethoxy-N-(4-(thiomorpholine-4-sulfonyl)-phenyl)-benzamide (described in patent publications DE19830430 and W02000002851); and
  • Heme-dependent, NO-independent sGC stimulators including, but not limited to:
  • PDE1 inhibitors, PDE2 inhibitors, PDE-3 inhibitors such as, for example, amrinone, milrinone, enoximone, vesnarinone, pimobendan, and olprinone
  • PDE4 inhibitors such as, for example, rolumilast
  • PDE5 inhibitors such as, for example, sildenafil (Viagra ® ) and related agents such as avanafil, lodenafil, mirodenafil, sildenafil citrate (Revatio®), tadalafil (Cialis ® or Adcirca®), vardenafil (Levitra ® ) and udenafil; alprostadil; dipyridamole and PF- 00489791; PDE6 inhibitors, PDE9 inhibitors, such as, for example, PF-04447943, PDE10 inhibitors such as, for example, PF-02545920 (PF-10), and PDE11 inhibitor
  • dihydropyridine calcium channel blockers such asamlodipine (Norvasc®), aranidipine (Sapresta®), azelnidipine (Calblock®), bamidipine (HypoCa®), benidipine (Coniel®), cilnidipine (Atelec®, Cinalong®, Siscard®), clevidipine (Cleviprex®), diltiazem, efonidipine (Landel®), felodipine (Plendil®), lacidipine (Motens®, Lacipil®), lercanidipine (Zanidip®), manidipine (Calslot®, Madipine®), nicardipine (Cardene®, Carden SR®), nifedipine (Procardia®, Adalat®), nilvadipine (Nivadil®), nimodipine (Nimotop ®), nisoldipine (Ba
  • phenylalkylamine calcium channel blockers such as verapamil (Calan®, Isoptin®); and gallopamil (Procorum®, D600);
  • benzothiazepines such asdiltiazem (Cardizem ®);
  • nonselective calcium channel inhibitors such as mibefradil, bepridil, fluspirilene, and fendiline.
  • Endothelin receptor antagonists such as the dual (ET A and ET B ) endothelin receptor antagonist bosentan (Tracleer®), sitaxentan (Thelin®) or ambrisentan (Letairis®).
  • Prostacyclin derivatives or analogues such asprostacyclin (prostaglandin I 2 ), epoprostenol (synthetic prostacyclin, Flolan®), treprostinil (Remodulin®), iloprost (Ilomedin®), iloprost (Ventavis®); and oral and inhaled forms of Remodulin® under development.
  • Antihyperlipidemics such as the following types:
  • bile acid sequestrants like cholestyramine, colestipol, colestilan, colesevelam or sevelamer;
  • statins like atorvastatin, simvastatin, lovastatin, fluvastatin, pitavastatin, rosuvastatin and pravastatin;
  • cholesterol absorption inhibitors such as ezetimibe
  • lipid lowering agents such as icosapent ethyl ester, omega-3-acid ethyl esters, reducol;
  • fibric acid derivatives such as clofibrate, bezafibrate, clinofibrate, gemfibrozil, ronifibrate, binifibrate, fenofibrate, ciprofibrate, choline fenofibrate;
  • nicotinic acid derivatives such as acipimox and niacin
  • statins niacin and intestinal cholesterol absorption-inhibiting supplements (ezetimibe and others) and fibrates;
  • antiplatelet therapies such as clopidogrel bisulfate.
  • Anticoagulants such as the following types:
  • Vitamin K antagonists such as warfarin (Coumadin ®), cenocoumarol, phenprocoumon and phenindione;
  • heparin and derivatives such as low molecular weight heparin, fondaparinux and idraparinux;
  • direct thrombin inhibitors such as argatroban, lepirudin, bivalirudin, dabigatran and ximelagatran (Exanta®); and
  • tissue-plasminogen activators used to dissolve clots and unblock arteries, such as alteplase.
  • Antiplatelet drugs such as, for instance, topidogrel, ticlopidine,
  • ACE inhibitors for example the following types:
  • sulfhydryl-containing agents such as captopril (Capoten®) and zofenopril;
  • dicarboxylate-containing agents such as enalapril (Vasotec/Renitec®), ramipril
  • phosphonate-containing agents such as fosinopril
  • naturally occurring ACE inhibitors such as casokinins and lactokinins, which are breakdown products of casein and whey that occur naturally after ingestion of milk products, especially cultured milk
  • ACE inhibitors such as casokinins and lactokinins, which are breakdown products of casein and whey that occur naturally after ingestion of milk products, especially cultured milk
  • ACE inhibitors such as alacepril, delapril, cilazapril, imidapril, trandolapril, temocapril, moexipril and pirapril.
  • Beta blockers such as the following types:
  • non-selective agents such as alprenolol, bucindolol, carteolol, carvedilol, labetalol, nadolol, penbutolol, pindolol, oxprenonol, acebutolol, sotalol, mepindolol, celiprolol, arotinolol, tertatolol, amosulalol, nipradilol, propranolol and timolol;
  • bi-Selective agents such as cebutolol, atenolol, betaxolol, bisoprolol, celiprolol, dobutamine hydrochloride, irsogladine maleate, carvedilol, talinolol, esmolol, metoprolol and nebivolol; and
  • P 2 -Selective agents such as butaxamine.
  • Antiarrhythmic agents such as the following types:
  • Type I sodium channel blockers
  • quinidine such as quinidine, lidocaine, phenytoin, propafenone
  • Type III potassium channel blockers
  • amiodarone such as amiodarone, dofetilide and sotalol
  • Type V such as adenosine and digoxin.
  • Diuretics such as thiazide diuretics, for example chlorothiazide, chlorthalidone and hydrochlorothiazide, bendroflumethiazide, cyclopenthiazide, methyclothiazide, polythiazide, quinethazone, xipamide, metolazone, indapamide, cicletanine; loop diuretics, such as furosemide and toresamide; potassium-sparing diuretics such as amiloride, spironolactone, canrenoate potassium, eplerenone and triamterene; combinations of these agents; other diuretics such as acetazolamid and carperitide.
  • thiazide diuretics for example chlorothiazide, chlorthalidone and hydrochlorothiazide, bendroflumethiazide, cyclopenthiazide, methyclothiazide, polythiazide, quinethazone, xip
  • vasodilators such as hydralazine hydrochloride, diazoxide, sodium nitroprusside, cadralazine; other vasodilators such as isosorbide dinitrate and isosorbide 5 -mononitrate.
  • Exogenous vasodilators such as Adenocard® and alpha blockers.
  • Alpha- 1 -adrenoceptor antagonists such as prazosin, indoramin, urapidil, bunazosin, terazosin and doxazosin; atrial natriuretic peptide (ANP), ethanol, histamine- inducers, tetrahydrocannabinol (THC) and papaverine.
  • short acting b 2 agonists such as albutamol or albuterol (Ventolin®) and terbutaline
  • long acting b 2 agonists such as salmeterol and formoterol
  • anticholinergics such as pratropium and tiotropium
  • theophylline a bronchodilator and phosphodiesterase inhibitor.
  • Corticosteroids such as beclomethasone, methylprednisolone, betamethasone, prednisone, prednisolone, triamcinolone, dexamethasone, fluticasone, flunisolide,
  • hydrocortisone and corticosteroid analogs such as budesonide.
  • Dietary supplements such as, for example omega-3 oils; folic acid, niacin, zinc, copper, Korean red ginseng root, ginkgo, pine bark, Tribulus terrestris, arginine, Avena sativa, horny goat weed, maca root, muira puama, saw palmetto, and Swedish flower pollen; vitamin C, Vitamin E, Vitamin K2; testosterone supplements, testosterone transdermal patch; zoraxel, naltrexone, bremelanotide and melanotan II.
  • Dietary supplements such as, for example omega-3 oils; folic acid, niacin, zinc, copper, Korean red ginseng root, ginkgo, pine bark, Tribulus terrestris, arginine, Avena sativa, horny goat weed, maca root, muira puama, saw palmetto, and Swedish flower pollen; vitamin C, Vitamin E, Vitamin K2; testosterone supplements, testosterone transderma
  • Immunosuppressants such as cyclosporine (cyclosporine A, Sandimmune®, Neoral®), tacrolimus (FK-506, Prograf®), rapamycin (Sirolimus®, Rapamune®) and other FK-506 type immunosuppressants, mycophenolate, e.g., mycophenolate mofetil (CellCept®).
  • Non-steroidal anti- asthmatics such as b2 ⁇ oh ⁇ 8 ⁇ 8 like terbutaline
  • metaproterenol fenoterol, isoetharine, albuterol, salmeterol, bitolterol and pirbuterol
  • b2- agonist-corticosteroid combinations such as salmeterol-fluticasone (Advair®), formoterol- budesonide (Symbicort®), theophylline, cromolyn, cromolyn sodium, nedocromil, atropine, ipratropium, ipratropium bromide and leukotriene biosynthesis inhibitors (zileuton,
  • Non-steroidal anti-inflammatory agents such as propionic acid derivatives like alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid and tioxaprofen); acetic acid derivatives such as indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidom
  • Cyclooxygenase-2 (COX-2) inhibitors such as celecoxib (Celebrex®), rofecoxib (Vioxx®), valdecoxib, etoricoxib, parecoxib and lumiracoxib; opioid analgesics such as codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyphene, buprenorphine, butorphanol, dezocine, nalbuphine and pentazocine;
  • COX-2 (COX-2) inhibitors such as celecoxib (Celebrex®), rofecoxib (Vioxx®), valdecoxib, etoricoxib, parecoxib and lumiracoxib
  • opioid analgesics such as codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine,
  • Anti-diabetic agents such as insulin and insulin mimetics; sulfonylureas such as glyburide, glybenclamide, glipizide, gliclazide, gliquidone, glimepiride, meglinatide, tolbutamide, chlorpropamide, acetohexamide and olazamide; biguanides such as metformin (Glucophage®); a-glucosidase inhibitors such as acarbose, epalrestat, voglibose, miglitol; thiazolidinone compounds such as rosiglitazone (Avandia®), troglitazone (Rezulin®), ciglitazone, pioglitazone (Actos®) and englitazone; insulin sensitizers such as pioglitazone and rosiglitazone; insulin secretagogues such as repaglinide, nateglinide
  • dipeptidyl peptidase IV inhibitors such as sitagliptin, vildagliptin, saxagliptin, alogliptin and linagliptin.
  • HDL cholesterol-increasing agents such as anacetrapib and dalcetrapib.
  • Antiobesity drugs such as methamphetamine hydrochloride, amfepramone hydrochloride (Tenuate ®), phentermine (Ionamin ®), benzfetamine hydrochloride (Didrex ®), phendimetrazine tartrate (Bontril®, Prelu-2 ®, Plegine ®), mazindol (Sanorex ®), orlistat (Xenical ®), sibutramine hydrochloride monohydrate (Meridia ®, Reductil ®), rimonabant (Acomplia ®), amfepramone, chromium picolinate; combination such as
  • SR/zonisamide SR salmeterol, xinafoate/fluticasone propionate; lorcaserin hydrochloride, phentermine/topiramate, cetilistat, exenatide, liraglutide, metformin hydrochloride, sibutramine/metformin, bupropion SR/zonisamide SR, CORT- 108297, canagliflozin, chromium picolinate, GSK-1521498, LY-377604, metreleptin, obinepitide, P-57AS3, PSN- 821, salmeterol xinafoate/fluticasone propionate, sodium tungstate, somatropin
  • Angiotensin receptor blockers such as losartan, valsartan, candesartan, cilexetil, eprosaran, irbesartan, telmisartan, olmesartran, medoxomil, azilsartan and medoxomil.
  • Renin inhibitors such as aliskiren hemifumirate.
  • Adrenergic neuron blockers such as guanethidine and guanadrel.
  • Imidazoline 1-1 receptor agonists such as rimenidine dihydrogen phosphate and moxonidine hydrochloride hydrate.
  • Aldosterone antagonists such as spironolactone and eplerenone.
  • Dopamine Dl agonists such as fenoldopam mesilate; other dopamine agonists such as ibopamine, dopexamine and docarpamine.
  • Vasopressin antagonists such as tolvaptan.
  • Calcium channel sensitizers such as levosimendan or activators such as nicorandil.
  • Adenylate cyclase activators such as colforsin dapropate hydrochloride.
  • Positive inotropic agents such as digoxin and metildigoxin; metabolic cardiotonic agents such as ubidecarenone; brain natriuretic peptides such as nesiritide.
  • Drugs used for the treatment of erectile dysfunction such as alprostadil, aviptadil, and phentolamine mesilate.
  • Drugs used in the treatment of obesity including but not limited to, methamphetamine hydrochloride (Desoxyn®), amfepramone hydrochloride (Tenuate®), phentermine (Ionamin®), benzfetamine hydrochloride (Didrex®), phendimetrazine hydrochloride (Bontril®, Prelu-2®, Plegine®), mazindol (Sanorex®) and orlistat (Xenical®).
  • Drugs used for the treatment of Alzheimer’s disease and dementias such as the following types: acetyl cholinesterase inhibitors including galantamine (Razadyne®), rivastigmine (Exelon®), donepezil (Aricept®) and tacrine (Cognex®); NMDA receptor antagonists such as memantine (Namenda®); and oxidoreductase inhibitors such as idebenone.
  • Psychiatric medications such as the following types:
  • ziprasidone (GeodonTM), risperidone (RisperdalTM), olanzapine (ZyprexaTM), valproate; dopamine D4 receptor antagonists such as clozapine;
  • dopamine D2 receptor antagonists such as nemonapride
  • mixed dopamine D1/D2 receptor antagonists such as zuclopenthixol
  • GABA A receptor modulators such as carbamazepine
  • sodium channel inhibitors such as lamotrigine
  • monoamine oxidase inhibitors such as moclobemide and indeloxazine; and primavanserin, and perospirone.
  • catechol-O-methyl transferase inhibitors such as entacapone
  • monoamine oxidase B inhibitors such as selegiline
  • dopamine receptor modulators such as levodopa
  • dopamine D3 receptor agonists such as pramipexole
  • decarboxylase inhibitors such as carbidopa
  • dopamine receptor agonists such as pergolide, ropinirole, cabergoline;
  • ritigonide istradefylline, talipexole; zonisamide and safinamide;
  • synaptic vesicular amine transporter inhibitors such as tetrabenazine.
  • tricyclic antidepressants such as amitriptyline (Elavil®), desipramine (Norpramin®), imipramine (Tofranil®), amoxapine (Asendin®), nortriptyline and clomipramine;
  • SSRIs selective serotonin reuptake inhibitors
  • Paxil® paroxetine
  • Prozac® fluoxetine
  • sertraline Zoloft®
  • citralopram citralopram
  • doxepin (Sinequan®), trazodone (Desyrel®) and agomelatine;
  • SNRIs selective norepinephrine reuptake inhibitors
  • venlafaxine venlafaxine
  • reboxetine atomoxetine
  • dopaminergic antidepressants such as bupropion and amineptine.
  • Drugs for the enhancement of synaptic plasticity such as the following types: nicotinic receptor antagonists such as mecamylamine; and
  • Drugs used for the treatment of ADHD such as amphetamine; 5-HT receptor modulators such as vortioxetine and alpha -2 adrenoceptor agonists such as clonidine.
  • Neutral endopeptidase (NEP) inhibitors such as sacubitril, omapatrilat; and Methylene blue (MB).
  • NEP Neutral endopeptidase
  • MB Methylene blue
  • Nitric oxide synthase cofactors such as: tetrahydrobiopterin, dihydrobiopterin, and sapropterin (Kuvan®)
  • the pharmaceutical composition (or formulation) for use may be packaged in a variety of ways depending upon the method used for administering the drug.
  • an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form.
  • Suitable containers are well-known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like.
  • the container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package.
  • the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.
  • the compounds and pharmaceutical formulations described herein may be contained in a kit.
  • the kit may include single or multiple doses of two or more agents, each packaged or formulated individually, or single or multiple doses of two or more agents packaged or formulated in combination.
  • one or more agents can be present in first container, and the kit can optionally include one or more agents in a second container.
  • the container or containers are placed within a package, and the package can optionally include administration or dosage instructions.
  • a kit can include additional components such as syringes or other means for administering the agents as well as diluents or other means for formulation.
  • kits can comprise: a) a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable carrier, vehicle or diluent; and b) a container or packaging.
  • the kits may optionally comprise instructions describing a method of using the pharmaceutical compositions in one or more of the methods described herein (e.g. preventing or treating one or more of the diseases and disorders described herein).
  • the kit may optionally comprise a second pharmaceutical composition comprising one or more additional agents described herein for co therapy use, a pharmaceutically acceptable carrier, vehicle or diluent.
  • the pharmaceutical composition comprising the compound described herein and the second pharmaceutical composition contained in the kit may be optionally combined in the same pharmaceutical composition.
  • the suspension was cooled to 8-l0°C and 0.06 eq. (60 mL) 1M aq. NaOH was added, followed by sat. aq. NaCl (150 mL) and DI water (200 mL). The resulting mixture was stirred for several hours, before adjusting the pH to 8-9 with 10% aq. sodium carbonate. The resulting mixture was then diluted with water (250 mL) and filtered over a 2L medium poros. glass frit, washed with DI water (3 x 300 mL), and suction dried on the filter for -45 min.
  • Form A can also be made by slurring (e.g ., mixing the compound with a solvent and stirring continuously) the compound of Formula (I) using a mixture of isopropyl acetate (IP AC) and n-heptane, where the n-heptane makes up more than 50% by volume of the composition for 24 hours to 1 week at room temperature.
  • Form A is also formed when 8-(2- fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine is suspended or recrystallized in the 100% n-heptane or cyclohexane.
  • IP A isopropyl alcohol
  • IP A/IP AC mixtures are examples of isopropyl alcohol
  • IPAC hexane
  • tetrahydrofuran examples include (a) isopropyl alcohol (IP A); (b) IP A/IP AC mixtures; (c) mixtures of IPAC and hexane with IPAC making up 50% or more by volume of the composition; and (d) tetrahydrofuran.
  • Hydrate 2 was crystallized by slurring anhydrous 8-(2-fluorobenzyl)-6-(3- (trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine (either Form A or Form B) in aqueous mixtures containing cellulose-based polymers such as methylcellulose and/or surfactants such as Tween 80 and sodium lauryl sulfate for 24 hours to 1 week at room temperature. Hydrate 2 can also be crystallized out of aqueous solutions containing 10% of organic solvents such as isopropyl alcohol.
  • Ethanol solvate was isolated by slurring 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)- lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine (either Form A or Form B) in 100% ethanol for 24 hours to 1 week at room temperature.
  • Methanol Solvate 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)- lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine (either Form A or Form B) in 100% ethanol for 24 hours to 1 week at room temperature.
  • Methanol solvate was isolated by slurring 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)- lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine (either Form A or Form B) in 100% methanol for 24 hours to 1 week at room temperature.
  • Methyl ethyl ketone solvate was isolated by slurring 8-(2-fluorobenzyl)-6-(3- (trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine (either Form A or Form B) in 100% methyl ethyl ketone for 24 hours to 1 week at room temperature.
  • Dichloromethane (DCM) solvate was isolated by slurring 8-(2-fluorobenzyl)-6-(3- (trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine (either Form A or Form B) in 100% DCM for 24 hours to 1 week at room temperature.
  • Acetonitrile (ACN) solvate was isolated by slurring 8-(2-fluorobenzyl)-6-(3- (trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine (either Form A or Form B) in 100% ACN for 24 hours to 1 week at room temperature.
  • the solvent was removed in vacuo and dried to a yellow residue.
  • the residue was taken up in AcOH (10 mL) and EtOH (100 mL) and heated at 90 °C for 1 hour.
  • the reaction mixture was cooled to ambient temperature and concentrated to half the reaction volume.
  • the resultant thick suspension was filtered, and the filtrate was concentrated to brown oil.
  • the crude material was purified using silica gel chromatography (10-100 % EtO Ac/hexanes gradient) to isolate the ethyl acetate solvate (4.0 g, 69 % yield) as a tan solid.
  • the ethyl acetate solvate was isolated by slurring 8-(2-fluorobenzyl)-6- (3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine (either Form A or Form B) in 100% ethyl acetate for 24 hours to 1 week at room temperature.
  • the XRPD patterns were acquired at room temperature in reflection mode using a Bruker D8 Discover system equipped with a sealed tube source and a Hi-Star area detector (Bruker AXS, Madison, WI).
  • the X-Ray generator was operated at a voltage of 40 kV and a current of 40 mA.
  • the powder sample was placed in a low-background holder.
  • the data was subsequently integrated over the range of 5.000° - 45.000° 20 with a step size of 0.020° and merged into one continuous pattern.
  • the X-ray powder diffraction pattern is made using CuKal radiation (Cu wavelength of l.54060nm).
  • the XRPD patterns are acquired at room temperature in reflection mode using a Panalytical Empyrean system equipped with a sealed tube source and a PIXcel 10 detector.
  • the X-Ray generator is operated at a voltage of 45 kV and a current of 40 mA.
  • the powder sample is placed in a zero-background holder. The data is
  • the X-ray powder diffraction pattern is made using CuKal radiation (Cu wavelength of l.54060nm).
  • the X-ray powder diffraction pattern (XRPD) of 8-(2-fluorobenzyl)-6-(3- (trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine Form A is shown in FIG. 1A.
  • the X-ray powder diffraction pattern (XRPD) of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)- lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine Form A is shown in FIG. 1B.
  • the XRPD pattern of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2- a]pyrazine Form B is shown in FIG. 5A.
  • the XRPD pattern of 8-(2-fluorobenzyl)-6-(3- (trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine Form B is shown in FIG. 5B.
  • the XRPD pattern of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5- yl)imidazo[l,2-a]pyrazine Hydrate 1 is shown in FIG. 8A.
  • the XRPD pattern of 8-(2- fluorobenzyl)-6-(3-(trifluoromethyl)- 1H- 1 ,2,4-triazol-5-yl)imidazo[ 1 ,2-a]pyrazine Hydrate 1 is shown in FIG. 8B.
  • the XRPD pattern of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine Hydrate 2 is shown in FIG 11 A.
  • the XRPD pattern of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2- a]pyrazine Hydrate 2 is shown in FIG 11B.
  • the XRPD pattern of 8-(2-fluorobenzyl)-6-(3- (trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine Hydrate 3 is shown in FIG. 14A.
  • the XRPD pattern of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5- yl)imidazo[l,2-a]pyrazine Hydrate 3 is shown in FIG. 14B.
  • the XRPD pattern of 8-(2- fluorobenzyl)-6-(3-(trifluoromethyl)- 1H- 1 ,2,4-triazol-5-yl)imidazo[ 1 ,2-a]pyrazine Ethanol Solvate is shown in FIG. 17.
  • the XRPD pattern of 8-(2-fluorobenzyl)-6-(3- (trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine Methanol Solvate is shown in FIG. 19.
  • the XRPD pattern of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5- yl)imidazo[l,2-a]pyrazine Methyl Ethyl Solvate is shown in FIG. 21.
  • the XRPD pattern of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine Dichloromethane Solvate is shown in FIG. 22.
  • the XRPD pattern of 8-(2-fluorobenzyl)-6- (3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine Acetonitrile Solvate is shown in FIG. 24.
  • the XRPD pattern of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- 1,2,4- triazol-5-yl)imidazo[l,2-a]pyrazine ethyl acetate solvate is shown in FIG. 26. Table 1A.
  • Table 1B XRPD peak list for 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5- yl)imidazo[l,2-a]pyrazine Form A, acquired at room temperature in reflection mode using a Panalytical Empyrean system described above.
  • Table 2A XRPD peak list for 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5- yl)imidazo[l,2-a]pyrazine Form B, acquired at room temperature in reflection mode using a Bruker D8 Discover system described above.
  • Table 2B XRPD peak list for 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- l,2,4-triazol-5- yl)imidazo[l,2-a]pyrazine Form B, acquired at room temperature in reflection mode using a Panalytical Empyrean system described above.
  • Table 3A XRPD peak list for 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5- yl)imidazo[l,2-a]pyrazine Hydrate 1, acquired at room temperature in reflection mode using a Bruker D8 Discover system described above.
  • Table 3B XRPD peak list for 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- l,2,4-triazol-5- yl)imidazo[l,2-a]pyrazine Hydrate 1, acquired at room temperature in reflection mode using a Panalytical Empyrean system described above.
  • Table 4A XRPD peak list for 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5- yl)imidazo[l,2-a]pyrazine Hydrate 2, acquired at room temperature in reflection mode using a Bruker D8 Discover system described above.
  • Table 4B XRPD peak list for 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- l,2,4-triazol-5- yl)imidazo[l,2-a]pyrazine Hydrate 2, acquired at room temperature in reflection mode using a Panalytical Empyrean system described above.
  • Table 5A XRPD peak list for 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5- yl)imidazo[l,2-a]pyrazine Hydrate 3, acquired at room temperature in reflection mode using a Bruker D8 Discover system described above.
  • Table 5B XRPD peak list for 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH- l,2,4-triazol-5- yl)imidazo[l,2-a]pyrazine Hydrate 3, acquired at room temperature in reflection mode using a Panalytical Empyrean system described above.
  • DSC Differential Scanning Calorimetry
  • Form B has an initial melting point at l77°C, which is followed by an immediate crystallization to anhydrous Form A, which melts at l96.4°C (FIG. 6).
  • Thermogravimetric Analysis (TGA) results for residual solids were obtained using the TA Instruments model Q5000 TGA V3.8 Build 256 Sample sizes of 2 to 10 mg were added to tared platinum sample pans and heated at 5°C/min from room temperature up to 250°C.
  • the data was analyzed with the Universal Analysis 2000 software.
  • the thermal gravimetric analysis (TGA) of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)- lH-l,2,4-triazol-5-yl)imidazo[l,2-a]pyrazine Form A indicates no weight loss until the melt, signifying that Form A is anhydrous (FIG. 3).
  • the TGA analysis of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-lH-l,2,4-triazol-5- yl)imidazo[l,2-a]pyrazine Form B indicates no weight loss until the melt, signifying that Form B is anhydrous (FIG. 7).
  • the Adsorption/Desorption determination was performed using a Q5000 V3.3 TGA- SA instrument.
  • the sample was dispensed on a tarred platinum pan and a ramp run from 10% relative humidity (RH) to 90% RH and then back down to 10% RH with 10% RH increments.
  • the ramp was isothermal at 25°C. Water was used as the solvent for all DVS analysis.
  • the data was analyzed with the Universal Analysis 2000 software.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention concerne des formes cristallines de 8-(2-fluorobenzyl)-6-(3- (trifluorométhyl)-1H-1,2,4-triazol-5-yl) imidazo[1, 2-a]pyrazine, qui sont utiles en tant que stimulateur de la guanylate cyclase soluble (sGC). La présente invention concerne également des compositions pharmaceutiquement acceptables comprenant les formes cristallines et des procédés d'utilisation desdites compositions dans le traitement de divers troubles.
PCT/US2019/021080 2018-03-07 2019-03-07 Formes cristallines d'un stimulateur de sgc WO2019173551A1 (fr)

Priority Applications (22)

Application Number Priority Date Filing Date Title
CA3092683A CA3092683A1 (fr) 2018-03-07 2019-03-07 Formes cristallines d'un stimulateur de sgc
CN201980017657.XA CN111836812A (zh) 2018-03-07 2019-03-07 sGC刺激剂的晶型
JP2020546378A JP7423539B2 (ja) 2018-03-07 2019-03-07 Ｓｇｃ刺激因子の結晶形態
MX2020009183A MX2020009183A (es) 2018-03-07 2019-03-07 Formas cristalinas de un estimulante de la guanilil ciclasa soluble (sgc).
US16/976,430 US11466015B2 (en) 2018-03-07 2019-03-07 Crystalline forms of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine as sGC stimulators
MX2023004856A MX2023004856A (es) 2018-03-07 2019-03-07 Formas cristalinas de un estimulante de la guanilil ciclasa soluble (sgc).
AU2019231724A AU2019231724B2 (en) 2018-03-07 2019-03-07 Crystalline forms of an sGC stimulator
KR1020207028170A KR20200128708A (ko) 2018-03-07 2019-03-07 sGC 자극제의 결정질 형태
SG11202008641WA SG11202008641WA (en) 2018-03-07 2019-03-07 Crystalline forms of an sgc stimulator
MX2023004857A MX2023004857A (es) 2018-03-07 2019-03-07 Formas cristalinas de un estimulante de la guanilil ciclasa soluble (sgc).
ES19712427T ES2980256T3 (es) 2018-03-07 2019-03-07 Formas cristalinas de un estimulador SGC
EP19712427.4A EP3762389B1 (fr) 2018-03-07 2019-03-07 Formes cristallines d'un stimulateur de sgc
CR20200458A CR20200458A (es) 2018-03-07 2019-03-07 FORMAS CRISTALINAS DE UN ESTIMULANTE DE LA GUANILIL CICLASA SOLUBLE (sGC)
PE2020001347A PE20210124A1 (es) 2018-03-07 2019-03-07 FORMAS CRISTALINAS DE UN ESTIMULANTE DE LA GUANILIL CICLASA SOLUBLE (sGC)
EA202092109A EA202092109A1 (ru) 2018-03-07 2019-03-07 КРИСТАЛЛИЧЕСКИЕ ФОРМЫ СТИМУЛЯТОРА sGC
BR112020018212-5A BR112020018212A2 (pt) 2018-03-07 2019-03-07 Formas cristalinas de um estimulante de sgc
MX2023004855A MX2023004855A (es) 2018-03-07 2019-03-07 Formas cristalinas de un estimulante de la guanilil ciclasa soluble (sgc).
MX2023004858A MX2023004858A (es) 2018-03-07 2019-03-07 Formas cristalinas de un estimulante de la guanilil ciclasa soluble (sgc).
IL276853A IL276853A (en) 2018-03-07 2020-08-20 Aggregate forms of SGC stimulator
PH12020551394A PH12020551394A1 (en) 2018-03-07 2020-09-05 CRYSTALLINE FORMS OF AN sGC STIMULATOR
CONC2020/0012493A CO2020012493A2 (es) 2018-03-07 2020-10-06 Formas cristalinas de un estimulante de la guanilil ciclasa soluble (sgc)
US17/954,713 US12122782B2 (en) 2022-09-28 Crystalline forms of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine as sGC stimulators

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201862639846P 2018-03-07 2018-03-07
US62/639,846 2018-03-07

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US202016976430A Continuation 2020-08-27 2020-08-27

Publications (2)

Publication Number Publication Date
WO2019173551A1 true WO2019173551A1 (fr) 2019-09-12
WO2019173551A8 WO2019173551A8 (fr) 2020-06-11

Family

ID=65818696

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2019/021080 WO2019173551A1 (fr) 2018-03-07 2019-03-07 Formes cristallines d'un stimulateur de sgc

Country Status (21)

Country Link
US (1) US11466015B2 (fr)
EP (1) EP3762389B1 (fr)
JP (1) JP7423539B2 (fr)
KR (1) KR20200128708A (fr)
CN (1) CN111836812A (fr)
AU (1) AU2019231724B2 (fr)
BR (1) BR112020018212A2 (fr)
CA (1) CA3092683A1 (fr)
CL (5) CL2020002284A1 (fr)
CO (1) CO2020012493A2 (fr)
CR (1) CR20200458A (fr)
EA (1) EA202092109A1 (fr)
ES (1) ES2980256T3 (fr)
IL (1) IL276853A (fr)
MA (1) MA54638A (fr)
MX (5) MX2023004858A (fr)
PE (1) PE20210124A1 (fr)
PH (1) PH12020551394A1 (fr)
SG (1) SG11202008641WA (fr)
TW (1) TWI823903B (fr)
WO (1) WO2019173551A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021195403A1 (fr) * 2020-03-26 2021-09-30 Cyclerion Therapeutics, Inc. Stimulateurs de sgc deutérés

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BR112021000358A2 (pt) * 2018-07-11 2021-04-06 Cyclerion Therapeutics, Inc. Uso de estimulantes de sgc para o tratamento de distúrbios mitocondriais
CN118221650A (zh) * 2022-12-21 2024-06-21 广东东阳光药业股份有限公司 氟取代的吲唑化合物的晶型及其用途
CN118221649A (zh) * 2022-12-21 2024-06-21 广东东阳光药业股份有限公司 氟取代的吲唑化合物的晶型及其用途

Citations (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0667345A1 (fr) 1994-02-14 1995-08-16 Yung Shin Pharm. Ind. Co. Ltd. Dérivés 1-benzyle-3-(aryle substitué) du pyrazole condensée comme agents inhibiteurs de l'aggrégation plaquettaire
DE19744026A1 (de) 1997-10-06 1999-04-08 Hoechst Marion Roussel De Gmbh Pyrazol-Derivate, ihre Herstellung und ihre Verwendung in Arzneimitteln
DE19830430A1 (de) 1998-07-08 2000-01-13 Hoechst Marion Roussel De Gmbh Schwefelsubstituierte Sulfonylamino-carbonsäure-N-arylamide, ihre Herstellung, ihre Verwendung und sie enthaltende pharmazeutische Präparate
WO2000002851A1 (fr) 1998-07-08 2000-01-20 Aventis Pharma Deutschland Gmbh N-arylamides d'acide sulfonylaminocarboxylique a substitution soufre, preparation et utilisation de ces derniers, preparations pharmaceutiques contenant ces composes
DE19834047A1 (de) 1998-07-29 2000-02-03 Bayer Ag Substituierte Pyrazolderivate
DE19834044A1 (de) 1998-07-29 2000-02-03 Bayer Ag Neue substituierte Pyrazolderivate
WO2000027394A1 (fr) 1998-11-05 2000-05-18 University College London Activateurs de guanylate cyclase soluble
DE19943635A1 (de) 1999-09-13 2001-03-15 Bayer Ag Neuartige Aminodicarbonsäurederivate mit pharmazeutischen Eigenschaften
DE19942809A1 (de) 1999-09-08 2001-03-15 Bayer Ag Verfahren zur Herstellung substituierter Pyrimidinderivate
WO2003086407A1 (fr) 2002-04-12 2003-10-23 Bayer Healthcare Ag Utilisation de stimulateurs de la guanylate cyclase soluble pour traiter le glaucome
WO2003095451A1 (fr) 2002-05-08 2003-11-20 Bayer Healthcare Ag Pyrazolopyridines a substitution carbamate
WO2009032249A1 (fr) 2007-09-06 2009-03-12 Merck & Co., Inc. Activateurs de la guanylate cyclase soluble
WO2009094242A1 (fr) 2008-01-24 2009-07-30 Merck & Co., Inc. Antagonistes du récepteur de l'angiotensine ii
WO2010065275A1 (fr) 2008-11-25 2010-06-10 Merck Sharp & Dohme Corp. Activateurs de guanylate cyclase soluble
US20100216764A1 (en) 2009-02-26 2010-08-26 Kim Ronald M Soluble Guanylate Cyclase Activators
WO2011119518A1 (fr) 2010-03-25 2011-09-29 Merck Sharp & Dohme Corp. Activateurs de guanylate cyclase solubles
WO2011149921A1 (fr) 2010-05-27 2011-12-01 Merck Sharp & Dohme Corp. Activateurs de guanylate cyclase soluble
WO2012058132A1 (fr) 2010-10-28 2012-05-03 Merck Sharp & Dohme Corp. Activateurs de la guanylate cyclase soluble
WO2015187470A1 (fr) 2014-06-04 2015-12-10 Merck Sharp & Dohme Corp. Dérivés d'imidazo-pyrazine utiles en tant qu'activateurs de guanylate cyclases solubles
WO2016087342A1 (fr) * 2014-12-02 2016-06-09 Bayer Pharma Aktiengesellschaft Pyrazolo[1,5-a]pyridines et imidazo[1,2-a]pyrazines substituées et leur utilisation
WO2018045276A1 (fr) * 2016-09-02 2018-03-08 Ironwood Pharmaceuticals, Inc. Stimulateurs sgc bicycliques fusionnés

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104327107A (zh) 2013-10-17 2015-02-04 广东东阳光药业有限公司 一种氟喹诺酮类抗菌药物的制备方法

Patent Citations (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0667345A1 (fr) 1994-02-14 1995-08-16 Yung Shin Pharm. Ind. Co. Ltd. Dérivés 1-benzyle-3-(aryle substitué) du pyrazole condensée comme agents inhibiteurs de l'aggrégation plaquettaire
DE19744026A1 (de) 1997-10-06 1999-04-08 Hoechst Marion Roussel De Gmbh Pyrazol-Derivate, ihre Herstellung und ihre Verwendung in Arzneimitteln
DE19830430A1 (de) 1998-07-08 2000-01-13 Hoechst Marion Roussel De Gmbh Schwefelsubstituierte Sulfonylamino-carbonsäure-N-arylamide, ihre Herstellung, ihre Verwendung und sie enthaltende pharmazeutische Präparate
WO2000002851A1 (fr) 1998-07-08 2000-01-20 Aventis Pharma Deutschland Gmbh N-arylamides d'acide sulfonylaminocarboxylique a substitution soufre, preparation et utilisation de ces derniers, preparations pharmaceutiques contenant ces composes
DE19834047A1 (de) 1998-07-29 2000-02-03 Bayer Ag Substituierte Pyrazolderivate
DE19834044A1 (de) 1998-07-29 2000-02-03 Bayer Ag Neue substituierte Pyrazolderivate
WO2000027394A1 (fr) 1998-11-05 2000-05-18 University College London Activateurs de guanylate cyclase soluble
DE19942809A1 (de) 1999-09-08 2001-03-15 Bayer Ag Verfahren zur Herstellung substituierter Pyrimidinderivate
DE19943635A1 (de) 1999-09-13 2001-03-15 Bayer Ag Neuartige Aminodicarbonsäurederivate mit pharmazeutischen Eigenschaften
WO2003086407A1 (fr) 2002-04-12 2003-10-23 Bayer Healthcare Ag Utilisation de stimulateurs de la guanylate cyclase soluble pour traiter le glaucome
WO2003095451A1 (fr) 2002-05-08 2003-11-20 Bayer Healthcare Ag Pyrazolopyridines a substitution carbamate
WO2009032249A1 (fr) 2007-09-06 2009-03-12 Merck & Co., Inc. Activateurs de la guanylate cyclase soluble
US20090209556A1 (en) 2007-09-06 2009-08-20 Bittner Amy R Soluble guanylate cyclase activators
US8455638B2 (en) 2007-09-06 2013-06-04 Merck Sharp & Dohme Corp. Soluble guanylate cyclase activators
US20110118282A1 (en) 2007-09-06 2011-05-19 Bittner Amy R Soluble Guanylate Cyclase Activators
WO2009094242A1 (fr) 2008-01-24 2009-07-30 Merck & Co., Inc. Antagonistes du récepteur de l'angiotensine ii
US8053455B2 (en) 2008-01-24 2011-11-08 Merck Sharp & Dohme Corp. Angiotensin II receptor antagonists
US20100292192A1 (en) 2008-01-24 2010-11-18 Amjad Ali Angiotensin ii receptor antagonists
US7947664B2 (en) 2008-01-24 2011-05-24 Merck Sharp & Dohme Corp. Angiotensin II receptor antagonists
US20110201621A1 (en) 2008-01-24 2011-08-18 Merck Sharp & Dohme Corp. Angiotensin ii receptor antagonists
WO2010065275A1 (fr) 2008-11-25 2010-06-10 Merck Sharp & Dohme Corp. Activateurs de guanylate cyclase soluble
US20110218202A1 (en) 2008-11-25 2011-09-08 Merck Sharp & Dohme Corp. Soluble guanylate cyclase activators
WO2010099054A2 (fr) 2009-02-26 2010-09-02 Merck Sharp & Dohme Corp. Activateurs solubles de guanylate cyclase
US20100216764A1 (en) 2009-02-26 2010-08-26 Kim Ronald M Soluble Guanylate Cyclase Activators
US8507512B2 (en) 2009-02-26 2013-08-13 Merck Sharp & Dohme Corp. Soluble guanylate cyclase activators
WO2011119518A1 (fr) 2010-03-25 2011-09-29 Merck Sharp & Dohme Corp. Activateurs de guanylate cyclase solubles
US20130012511A1 (en) 2010-03-25 2013-01-10 Darby Schmidt Soluble guanylate cyclase activators
WO2011149921A1 (fr) 2010-05-27 2011-12-01 Merck Sharp & Dohme Corp. Activateurs de guanylate cyclase soluble
US20130072492A1 (en) 2010-05-27 2013-03-21 Subharekha Raghavan Soluble guanylate cyclase activators
WO2012058132A1 (fr) 2010-10-28 2012-05-03 Merck Sharp & Dohme Corp. Activateurs de la guanylate cyclase soluble
US20130210798A1 (en) 2010-10-28 2013-08-15 John Q. Tan Soluble guanylate cyclase activators
WO2015187470A1 (fr) 2014-06-04 2015-12-10 Merck Sharp & Dohme Corp. Dérivés d'imidazo-pyrazine utiles en tant qu'activateurs de guanylate cyclases solubles
WO2016087342A1 (fr) * 2014-12-02 2016-06-09 Bayer Pharma Aktiengesellschaft Pyrazolo[1,5-a]pyridines et imidazo[1,2-a]pyrazines substituées et leur utilisation
WO2018045276A1 (fr) * 2016-09-02 2018-03-08 Ironwood Pharmaceuticals, Inc. Stimulateurs sgc bicycliques fusionnés

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
LEE R ROBERTS ET AL: "Acidic triazoles as soluble guanylate cyclase stimulators", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, AMSTERDAM, NL, vol. 21, no. 21, 13 August 2011 (2011-08-13), pages 6515 - 6518, XP028308807, ISSN: 0960-894X, [retrieved on 20110828], DOI: 10.1016/J.BMCL.2011.08.071 *
TETRAHEDRON LETTERS, vol. 44, no. 48, 2003, pages 8661 - 8663

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021195403A1 (fr) * 2020-03-26 2021-09-30 Cyclerion Therapeutics, Inc. Stimulateurs de sgc deutérés

Also Published As

Publication number Publication date
MX2023004856A (es) 2023-11-24
CL2021003530A1 (es) 2022-08-19
WO2019173551A8 (fr) 2020-06-11
CN111836812A (zh) 2020-10-27
KR20200128708A (ko) 2020-11-16
EP3762389A1 (fr) 2021-01-13
CL2021003536A1 (es) 2022-08-19
US11466015B2 (en) 2022-10-11
MX2023004857A (es) 2023-11-24
MX2020009183A (es) 2020-10-08
AU2019231724B2 (en) 2024-06-27
TW201940487A (zh) 2019-10-16
PH12020551394A1 (en) 2021-11-22
ES2980256T3 (es) 2024-09-30
MX2023004855A (es) 2023-11-24
IL276853A (en) 2020-10-29
MA54638A (fr) 2021-11-10
US20210115050A1 (en) 2021-04-22
MX2023004858A (es) 2023-11-24
JP7423539B2 (ja) 2024-01-29
JP2021515015A (ja) 2021-06-17
CO2020012493A2 (es) 2020-10-30
SG11202008641WA (en) 2020-10-29
CL2020002284A1 (es) 2020-11-27
EA202092109A1 (ru) 2021-03-04
AU2019231724A1 (en) 2020-10-08
CL2021000301A1 (es) 2021-06-18
BR112020018212A2 (pt) 2020-12-29
US20230095799A1 (en) 2023-03-30
TWI823903B (zh) 2023-12-01
CL2021003531A1 (es) 2022-08-19
PE20210124A1 (es) 2021-01-19
CR20200458A (es) 2020-11-09
EP3762389B1 (fr) 2024-02-28
CA3092683A1 (fr) 2019-09-12

Similar Documents

Publication Publication Date Title
US11572358B2 (en) Solid forms of an sGC stimulator
AU2019231724B2 (en) Crystalline forms of an sGC stimulator
AU2018388629B2 (en) sGC stimulators
AU2022200331B2 (en) Phosphorus prodrugs of sGC stimulators
US12122782B2 (en) Crystalline forms of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine as sGC stimulators
WO2021195403A1 (fr) Stimulateurs de sgc deutérés
US20240360164A1 (en) Phosphorus prodrugs of pyrazolo-substituted pyrimidine sgc stimulators
OA19465A (en) Solid forms of an SGC stimulator.

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19712427

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 3092683

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2020546378

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 20207028170

Country of ref document: KR

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2019231724

Country of ref document: AU

Date of ref document: 20190307

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2019712427

Country of ref document: EP

Effective date: 20201007

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112020018212

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 112020018212

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20200904